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PubMed Central Canada to be taken offline in February 2018

On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) 
Klionsky, Daniel J | Abdelmohsen, Kotb | Abe, Akihisa | Abedin, Md Joynal | Abeliovich, Hagai | Acevedo Arozena, Abraham | Adachi, Hiroaki | Adams, Christopher M | Adams, Peter D | Adeli, Khosrow | Adhihetty, Peter J | Adler, Sharon G | Agam, Galila | Agarwal, Rajesh | Aghi, Manish K | Agnello, Maria | Agostinis, Patrizia | Aguilar, Patricia V | Aguirre-Ghiso, Julio | Airoldi, Edoardo M | Ait-Si-Ali, Slimane | Akematsu, Takahiko | Akporiaye, Emmanuel T | Al-Rubeai, Mohamed | Albaiceta, Guillermo M | Albanese, Chris | Albani, Diego | Albert, Matthew L | Aldudo, Jesus | Algül, Hana | Alirezaei, Mehrdad | Alloza, Iraide | Almasan, Alexandru | Almonte-Beceril, Maylin | Alnemri, Emad S | Alonso, Covadonga | Altan-Bonnet, Nihal | Altieri, Dario C | Alvarez, Silvia | Alvarez-Erviti, Lydia | Alves, Sandro | Amadoro, Giuseppina | Amano, Atsuo | Amantini, Consuelo | Ambrosio, Santiago | Amelio, Ivano | Amer, Amal O | Amessou, Mohamed | Amon, Angelika | An, Zhenyi | Anania, Frank A | Andersen, Stig U | Andley, Usha P | Andreadi, Catherine K | Andrieu-Abadie, Nathalie | Anel, Alberto | Ann, David K | Anoopkumar-Dukie, Shailendra | Antonioli, Manuela | Aoki, Hiroshi | Apostolova, Nadezda | Aquila, Saveria | Aquilano, Katia | Araki, Koichi | Arama, Eli | Aranda, Agustin | Araya, Jun | Arcaro, Alexandre | Arias, Esperanza | Arimoto, Hirokazu | Ariosa, Aileen R | Armstrong, Jane L | Arnould, Thierry | Arsov, Ivica | Asanuma, Katsuhiko | Askanas, Valerie | Asselin, Eric | Atarashi, Ryuichiro | Atherton, Sally S | Atkin, Julie D | Attardi, Laura D | Auberger, Patrick | Auburger, Georg | Aurelian, Laure | Autelli, Riccardo | Avagliano, Laura | Avantaggiati, Maria Laura | Avrahami, Limor | Awale, Suresh | Azad, Neelam | Bachetti, Tiziana | Backer, Jonathan M | Bae, Dong-Hun | Bae, Jae-sung | Bae, Ok-Nam | Bae, Soo Han | Baehrecke, Eric H | Baek, Seung-Hoon | Baghdiguian, Stephen | Bagniewska-Zadworna, Agnieszka | Bai, Hua | Bai, Jie | Bai, Xue-Yuan | Bailly, Yannick | Balaji, Kithiganahalli Narayanaswamy | Balduini, Walter | Ballabio, Andrea | Balzan, Rena | Banerjee, Rajkumar | Bánhegyi, Gábor | Bao, Haijun | Barbeau, Benoit | Barrachina, Maria D | Barreiro, Esther | Bartel, Bonnie | Bartolomé, Alberto | Bassham, Diane C | Bassi, Maria Teresa | Bast, Robert C | Basu, Alakananda | Batista, Maria Teresa | Batoko, Henri | Battino, Maurizio | Bauckman, Kyle | Baumgarner, Bradley L | Bayer, K Ulrich | Beale, Rupert | Beaulieu, Jean-François | Beck, George R. | Becker, Christoph | Beckham, J David | Bédard, Pierre-André | Bednarski, Patrick J | Begley, Thomas J | Behl, Christian | Behrends, Christian | Behrens, Georg MN | Behrns, Kevin E | Bejarano, Eloy | Belaid, Amine | Belleudi, Francesca | Bénard, Giovanni | Berchem, Guy | Bergamaschi, Daniele | Bergami, Matteo | Berkhout, Ben | Berliocchi, Laura | Bernard, Amélie | Bernard, Monique | Bernassola, Francesca | Bertolotti, Anne | Bess, Amanda S | Besteiro, Sébastien | Bettuzzi, Saverio | Bhalla, Savita | Bhattacharyya, Shalmoli | Bhutia, Sujit K | Biagosch, Caroline | Bianchi, Michele Wolfe | Biard-Piechaczyk, Martine | Billes, Viktor | Bincoletto, Claudia | Bingol, Baris | Bird, Sara W | Bitoun, Marc | Bjedov, Ivana | Blackstone, Craig | Blanc, Lionel | Blanco, Guillermo A | Blomhoff, Heidi Kiil | Boada-Romero, Emilio | Böckler, Stefan | Boes, Marianne | Boesze-Battaglia, Kathleen | Boise, Lawrence H | Bolino, Alessandra | Boman, Andrea | Bonaldo, Paolo | Bordi, Matteo | Bosch, Jürgen | Botana, Luis M | Botti, Joelle | Bou, German | Bouché, Marina | Bouchecareilh, Marion | Boucher, Marie-Josée | Boulton, Michael E | Bouret, Sebastien G | Boya, Patricia | Boyer-Guittaut, Michaël | Bozhkov, Peter V | Brady, Nathan | Braga, Vania MM | Brancolini, Claudio | Braus, Gerhard H | Bravo-San Pedro, José M | Brennan, Lisa A | Bresnick, Emery H | Brest, Patrick | Bridges, Dave | Bringer, Marie-Agnès | Brini, Marisa | Brito, Glauber C | Brodin, Bertha | Brookes, Paul S | Brown, Eric J | Brown, Karen | Broxmeyer, Hal E | Bruhat, Alain | Brum, Patricia Chakur | Brumell, John H | Brunetti-Pierri, Nicola | Bryson-Richardson, Robert J | Buch, Shilpa | Buchan, Alastair M | Budak, Hikmet | Bulavin, Dmitry V | Bultman, Scott J | Bultynck, Geert | Bumbasirevic, Vladimir | Burelle, Yan | Burke, Robert E | Burmeister, Margit | Bütikofer, Peter | Caberlotto, Laura | Cadwell, Ken | Cahova, Monika | Cai, Dongsheng | Cai, Jingjing | Cai, Qian | Calatayud, Sara | Camougrand, Nadine | Campanella, Michelangelo | Campbell, Grant R | Campbell, Matthew | Campello, Silvia | Candau, Robin | Caniggia, Isabella | Cantoni, Lavinia | Cao, Lizhi | Caplan, Allan B | Caraglia, Michele | Cardinali, Claudio | Cardoso, Sandra Morais | Carew, Jennifer S | Carleton, Laura A | Carlin, Cathleen R | Carloni, Silvia | Carlsson, Sven R | Carmona-Gutierrez, Didac | Carneiro, Leticia AM | Carnevali, Oliana | Carra, Serena | Carrier, Alice | Carroll, Bernadette | Casas, Caty | Casas, Josefina | Cassinelli, Giuliana | Castets, Perrine | Castro-Obregon, Susana | Cavallini, Gabriella | Ceccherini, Isabella | Cecconi, Francesco | Cederbaum, Arthur I | Ceña, Valentín | Cenci, Simone | Cerella, Claudia | Cervia, Davide | Cetrullo, Silvia | Chaachouay, Hassan | Chae, Han-Jung | Chagin, Andrei S | Chai, Chee-Yin | Chakrabarti, Gopal | Chamilos, Georgios | Chan, Edmond YW | Chan, Matthew TV | Chandra, Dhyan | Chandra, Pallavi | Chang, Chih-Peng | Chang, Raymond Chuen-Chung | Chang, Ta Yuan | Chatham, John C | Chatterjee, Saurabh | Chauhan, Santosh | Che, Yongsheng | Cheetham, Michael E | Cheluvappa, Rajkumar | Chen, Chun-Jung | Chen, Gang | Chen, Guang-Chao | Chen, Guoqiang | Chen, Hongzhuan | Chen, Jeff W | Chen, Jian-Kang | Chen, Min | Chen, Mingzhou | Chen, Peiwen | Chen, Qi | Chen, Quan | Chen, Shang-Der | Chen, Si | Chen, Steve S-L | Chen, Wei | Chen, Wei-Jung | Chen, Wen Qiang | Chen, Wenli | Chen, Xiangmei | Chen, Yau-Hung | Chen, Ye-Guang | Chen, Yin | Chen, Yingyu | Chen, Yongshun | Chen, Yu-Jen | Chen, Yue-Qin | Chen, Yujie | Chen, Zhen | Chen, Zhong | Cheng, Alan | Cheng, Christopher HK | Cheng, Hua | Cheong, Heesun | Cherry, Sara | Chesney, Jason | Cheung, Chun Hei Antonio | Chevet, Eric | Chi, Hsiang Cheng | Chi, Sung-Gil | Chiacchiera, Fulvio | Chiang, Hui-Ling | Chiarelli, Roberto | Chiariello, Mario | Chieppa, Marcello | Chin, Lih-Shen | Chiong, Mario | Chiu, Gigi NC | Cho, Dong-Hyung | Cho, Ssang-Goo | Cho, William C | Cho, Yong-Yeon | Cho, Young-Seok | Choi, Augustine MK | Choi, Eui-Ju | Choi, Eun-Kyoung | Choi, Jayoung | Choi, Mary E | Choi, Seung-Il | Chou, Tsui-Fen | Chouaib, Salem | Choubey, Divaker | Choubey, Vinay | Chow, Kuan-Chih | Chowdhury, Kamal | Chu, Charleen T | Chuang, Tsung-Hsien | Chun, Taehoon | Chung, Hyewon | Chung, Taijoon | Chung, Yuen-Li | Chwae, Yong-Joon | Cianfanelli, Valentina | Ciarcia, Roberto | Ciechomska, Iwona A | Ciriolo, Maria Rosa | Cirone, Mara | Claerhout, Sofie | Clague, Michael J | Clària, Joan | Clarke, Peter GH | Clarke, Robert | Clementi, Emilio | Cleyrat, Cédric | Cnop, Miriam | Coccia, Eliana M | Cocco, Tiziana | Codogno, Patrice | Coers, Jörn | Cohen, Ezra EW | Colecchia, David | Coletto, Luisa | Coll, Núria S | Colucci-Guyon, Emma | Comincini, Sergio | Condello, Maria | Cook, Katherine L | Coombs, Graham H | Cooper, Cynthia D | Cooper, J Mark | Coppens, Isabelle | Corasaniti, Maria Tiziana | Corazzari, Marco | Corbalan, Ramon | Corcelle-Termeau, Elisabeth | Cordero, Mario D | Corral-Ramos, Cristina | Corti, Olga | Cossarizza, Andrea | Costelli, Paola | Costes, Safia | Cotman, Susan L | Coto-Montes, Ana | Cottet, Sandra | Couve, Eduardo | Covey, Lori R | Cowart, L Ashley | Cox, Jeffery S | Coxon, Fraser P | Coyne, Carolyn B | Cragg, Mark S | Craven, Rolf J | Crepaldi, Tiziana | Crespo, Jose L | Criollo, Alfredo | Crippa, Valeria | Cruz, Maria Teresa | Cuervo, Ana Maria | Cuezva, Jose M | Cui, Taixing | Cutillas, Pedro R | Czaja, Mark J | Czyzyk-Krzeska, Maria F | Dagda, Ruben K | Dahmen, Uta | Dai, Chunsun | Dai, Wenjie | Dai, Yun | Dalby, Kevin N | Dalla Valle, Luisa | Dalmasso, Guillaume | D'Amelio, Marcello | Damme, Markus | Darfeuille-Michaud, Arlette | Dargemont, Catherine | Darley-Usmar, Victor M | Dasarathy, Srinivasan | Dasgupta, Biplab | Dash, Srikanta | Dass, Crispin R | Davey, Hazel Marie | Davids, Lester M | Dávila, David | Davis, Roger J | Dawson, Ted M | Dawson, Valina L | Daza, Paula | de Belleroche, Jackie | de Figueiredo, Paul | de Figueiredo, Regina Celia Bressan Queiroz | de la Fuente, José | De Martino, Luisa | De Matteis, Antonella | De Meyer, Guido RY | De Milito, Angelo | De Santi, Mauro | de Souza, Wanderley | De Tata, Vincenzo | De Zio, Daniela | Debnath, Jayanta | Dechant, Reinhard | Decuypere, Jean-Paul | Deegan, Shane | Dehay, Benjamin | Del Bello, Barbara | Del Re, Dominic P | Delage-Mourroux, Régis | Delbridge, Lea MD | Deldicque, Louise | Delorme-Axford, Elizabeth | Deng, Yizhen | Dengjel, Joern | Denizot, Melanie | Dent, Paul | Der, Channing J | Deretic, Vojo | Derrien, Benoît | Deutsch, Eric | Devarenne, Timothy P | Devenish, Rodney J | Di Bartolomeo, Sabrina | Di Daniele, Nicola | Di Domenico, Fabio | Di Nardo, Alessia | Di Paola, Simone | Di Pietro, Antonio | Di Renzo, Livia | DiAntonio, Aaron | Díaz-Araya, Guillermo | Díaz-Laviada, Ines | Diaz-Meco, Maria T | Diaz-Nido, Javier | Dickey, Chad A | Dickson, Robert C | Diederich, Marc | Digard, Paul | Dikic, Ivan | Dinesh-Kumar, Savithrama P | Ding, Chan | Ding, Wen-Xing | Ding, Zufeng | Dini, Luciana | Distler, Jörg HW | Diwan, Abhinav | Djavaheri-Mergny, Mojgan | Dmytruk, Kostyantyn | Dobson, Renwick CJ | Doetsch, Volker | Dokladny, Karol | Dokudovskaya, Svetlana | Donadelli, Massimo | Dong, X Charlie | Dong, Xiaonan | Dong, Zheng | Donohue, Terrence M | Doran, Kelly S | D'Orazi, Gabriella | Dorn, Gerald W | Dosenko, Victor | Dridi, Sami | Drucker, Liat | Du, Jie | Du, Li-Lin | Du, Lihuan | du Toit, André | Dua, Priyamvada | Duan, Lei | Duann, Pu | Dubey, Vikash Kumar | Duchen, Michael R | Duchosal, Michel A | Duez, Helene | Dugail, Isabelle | Dumit, Verónica I | Duncan, Mara C | Dunlop, Elaine A | Dunn, William A | Dupont, Nicolas | Dupuis, Luc | Durán, Raúl V | Durcan, Thomas M | Duvezin-Caubet, Stéphane | Duvvuri, Umamaheswar | Eapen, Vinay | Ebrahimi-Fakhari, Darius | Echard, Arnaud | Eckhart, Leopold | Edelstein, Charles L | Edinger, Aimee L | Eichinger, Ludwig | Eisenberg, Tobias | Eisenberg-Lerner, Avital | Eissa, N Tony | El-Deiry, Wafik S | El-Khoury, Victoria | Elazar, Zvulun | Eldar-Finkelman, Hagit | Elliott, Chris JH | Emanuele, Enzo | Emmenegger, Urban | Engedal, Nikolai | Engelbrecht, Anna-Mart | Engelender, Simone | Enserink, Jorrit M | Erdmann, Ralf | Erenpreisa, Jekaterina | Eri, Rajaraman | Eriksen, Jason L | Erman, Andreja | Escalante, Ricardo | Eskelinen, Eeva-Liisa | Espert, Lucile | Esteban-Martínez, Lorena | Evans, Thomas J | Fabri, Mario | Fabrias, Gemma | Fabrizi, Cinzia | Facchiano, Antonio | Færgeman, Nils J | Faggioni, Alberto | Fairlie, W Douglas | Fan, Chunhai | Fan, Daping | Fan, Jie | Fang, Shengyun | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Faure, Mathias | Favier, Francois B | Fearnhead, Howard | Federici, Massimo | Fei, Erkang | Felizardo, Tania C | Feng, Hua | Feng, Yibin | Feng, Yuchen | Ferguson, Thomas A | Fernández, Álvaro F | Fernandez-Barrena, Maite G | Fernandez-Checa, Jose C | Fernández-López, Arsenio | Fernandez-Zapico, Martin E | Feron, Olivier | Ferraro, Elisabetta | Ferreira-Halder, Carmen Veríssima | Fesus, Laszlo | Feuer, Ralph | Fiesel, Fabienne C | Filippi-Chiela, Eduardo C | Filomeni, Giuseppe | Fimia, Gian Maria | Fingert, John H | Finkbeiner, Steven | Finkel, Toren | Fiorito, Filomena | Fisher, Paul B | Flajolet, Marc | Flamigni, Flavio | Florey, Oliver | Florio, Salvatore | Floto, R Andres | Folini, Marco | Follo, Carlo | Fon, Edward A | Fornai, Francesco | Fortunato, Franco | Fraldi, Alessandro | Franco, Rodrigo | Francois, Arnaud | François, Aurélie | Frankel, Lisa B | Fraser, Iain DC | Frey, Norbert | Freyssenet, Damien G | Frezza, Christian | Friedman, Scott L | Frigo, Daniel E | Fu, Dongxu | Fuentes, José M | Fueyo, Juan | Fujitani, Yoshio | Fujiwara, Yuuki | Fujiya, Mikihiro | Fukuda, Mitsunori | Fulda, Simone | Fusco, Carmela | Gabryel, Bozena | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galadari, Sehamuddin | Galili, Gad | Galindo, Inmaculada | Galindo, Maria F | Galliciotti, Giovanna | Galluzzi, Lorenzo | Galluzzi, Luca | Galy, Vincent | Gammoh, Noor | Gandy, Sam | Ganesan, Anand K | Ganesan, Swamynathan | Ganley, Ian G | Gannagé, Monique | Gao, Fen-Biao | Gao, Feng | Gao, Jian-Xin | García Nannig, Lorena | García Véscovi, Eleonora | Garcia-Macía, Marina | Garcia-Ruiz, Carmen | Garg, Abhishek D | Garg, Pramod Kumar | Gargini, Ricardo | Gassen, Nils Christian | Gatica, Damián | Gatti, Evelina | Gavard, Julie | Gavathiotis, Evripidis | Ge, Liang | Ge, Pengfei | Ge, Shengfang | Gean, Po-Wu | Gelmetti, Vania | Genazzani, Armando A | Geng, Jiefei | Genschik, Pascal | Gerner, Lisa | Gestwicki, Jason E | Gewirtz, David A | Ghavami, Saeid | Ghigo, Eric | Ghosh, Debabrata | Giammarioli, Anna Maria | Giampieri, Francesca | Giampietri, Claudia | Giatromanolaki, Alexandra | Gibbings, Derrick J | Gibellini, Lara | Gibson, Spencer B | Ginet, Vanessa | Giordano, Antonio | Giorgini, Flaviano | Giovannetti, Elisa | Girardin, Stephen E | Gispert, Suzana | Giuliano, Sandy | Gladson, Candece L | Glavic, Alvaro | Gleave, Martin | Godefroy, Nelly | Gogal, Robert M | Gokulan, Kuppan | Goldman, Gustavo H | Goletti, Delia | Goligorsky, Michael S | Gomes, Aldrin V | Gomes, Ligia C | Gomez, Hernando | Gomez-Manzano, Candelaria | Gómez-Sánchez, Rubén | Gonçalves, Dawit AP | Goncu, Ebru | Gong, Qingqiu | Gongora, Céline | Gonzalez, Carlos B | Gonzalez-Alegre, Pedro | Gonzalez-Cabo, Pilar | González-Polo, Rosa Ana | Goping, Ing Swie | Gorbea, Carlos | Gorbunov, Nikolai V | Goring, Daphne R | Gorman, Adrienne M | Gorski, Sharon M | Goruppi, Sandro | Goto-Yamada, Shino | Gotor, Cecilia | Gottlieb, Roberta A | Gozes, Illana | Gozuacik, Devrim | Graba, Yacine | Graef, Martin | Granato, Giovanna E | Grant, Gary Dean | Grant, Steven | Gravina, Giovanni Luca | Green, Douglas R | Greenhough, Alexander | Greenwood, Michael T | Grimaldi, Benedetto | Gros, Frédéric | Grose, Charles | Groulx, Jean-Francois | Gruber, Florian | Grumati, Paolo | Grune, Tilman | Guan, Jun-Lin | Guan, Kun-Liang | Guerra, Barbara | Guillen, Carlos | Gulshan, Kailash | Gunst, Jan | Guo, Chuanyong | Guo, Lei | Guo, Ming | Guo, Wenjie | Guo, Xu-Guang | Gust, Andrea A | Gustafsson, Åsa B | Gutierrez, Elaine | Gutierrez, Maximiliano G | Gwak, Ho-Shin | Haas, Albert | Haber, James E | Hadano, Shinji | Hagedorn, Monica | Hahn, David R | Halayko, Andrew J | Hamacher-Brady, Anne | Hamada, Kozo | Hamai, Ahmed | Hamann, Andrea | Hamasaki, Maho | Hamer, Isabelle | Hamid, Qutayba | Hammond, Ester M | Han, Feng | Han, Weidong | Handa, James T | Hanover, John A | Hansen, Malene | Harada, Masaru | Harhaji-Trajkovic, Ljubica | Harper, J Wade | Harrath, Abdel Halim | Harris, Adrian L | Harris, James | Hasler, Udo | Hasselblatt, Peter | Hasui, Kazuhisa | Hawley, Robert G | Hawley, Teresa S | He, Congcong | He, Cynthia Y | He, Fengtian | He, Gu | He, Rong-Rong | He, Xian-Hui | He, You-Wen | He, Yu-Ying | Heath, Joan K | Hébert, Marie-Josée | Heinzen, Robert A | Helgason, Gudmundur Vignir | Hensel, Michael | Henske, Elizabeth P | Her, Chengtao | Herman, Paul K | Hernández, Agustín | Hernandez, Carlos | Hernández-Tiedra, Sonia | Hetz, Claudio | Hiesinger, P Robin | Higaki, Katsumi | Hilfiker, Sabine | Hill, Bradford G | Hill, Joseph A | Hill, William D | Hino, Keisuke | Hofius, Daniel | Hofman, Paul | Höglinger, Günter U | Höhfeld, Jörg | Holz, Marina K | Hong, Yonggeun | Hood, David A | Hoozemans, Jeroen JM | Hoppe, Thorsten | Hsu, Chin | Hsu, Chin-Yuan | Hsu, Li-Chung | Hu, Dong | Hu, Guochang | Hu, Hong-Ming | Hu, Hongbo | Hu, Ming Chang | Hu, Yu-Chen | Hu, Zhuo-Wei | Hua, Fang | Hua, Ya | Huang, Canhua | Huang, Huey-Lan | Huang, Kuo-How | Huang, Kuo-Yang | Huang, Shile | Huang, Shiqian | Huang, Wei-Pang | Huang, Yi-Ran | Huang, Yong | Huang, Yunfei | Huber, Tobias B | Huebbe, Patricia | Huh, Won-Ki | Hulmi, Juha J | Hur, Gang Min | Hurley, James H | Husak, Zvenyslava | Hussain, Sabah NA | Hussain, Salik | Hwang, Jung Jin | Hwang, Seungmin | Hwang, Thomas IS | Ichihara, Atsuhiro | Imai, Yuzuru | Imbriano, Carol | Inomata, Megumi | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L | Iozzo, Renato V | Ip, Nancy Y | Irazoqui, Javier E | Iribarren, Pablo | Isaka, Yoshitaka | Isakovic, Aleksandra J | Ischiropoulos, Harry | Isenberg, Jeffrey S | Ishaq, Mohammad | Ishida, Hiroyuki | Ishii, Isao | Ishmael, Jane E | Isidoro, Ciro | Isobe, Ken-ichi | Isono, Erika | Issazadeh-Navikas, Shohreh | Itahana, Koji | Itakura, Eisuke | Ivanov, Andrei I | Iyer, Anand Krishnan V | Izquierdo, José M | Izumi, Yotaro | Izzo, Valentina | Jäättelä, Marja | Jaber, Nadia | Jackson, Daniel John | Jackson, William T | Jacob, Tony George | Jacques, Thomas S | Jagannath, Chinnaswamy | Jain, Ashish | Jana, Nihar Ranjan | Jang, Byoung Kuk | Jani, Alkesh | Janji, Bassam | Jannig, Paulo Roberto | Jansson, Patric J | Jean, Steve | Jendrach, Marina | Jeon, Ju-Hong | Jessen, Niels | Jeung, Eui-Bae | Jia, Kailiang | Jia, Lijun | Jiang, Hong | Jiang, Hongchi | Jiang, Liwen | Jiang, Teng | Jiang, Xiaoyan | Jiang, Xuejun | Jiang, Xuejun | Jiang, Ying | Jiang, Yongjun | Jiménez, Alberto | Jin, Cheng | Jin, Hongchuan | Jin, Lei | Jin, Meiyan | Jin, Shengkan | Jinwal, Umesh Kumar | Jo, Eun-Kyeong | Johansen, Terje | Johnson, Daniel E | Johnson, Gail VW | Johnson, James D | Jonasch, Eric | Jones, Chris | Joosten, Leo AB | Jordan, Joaquin | Joseph, Anna-Maria | Joseph, Bertrand | Joubert, Annie M | Ju, Dianwen | Ju, Jingfang | Juan, Hsueh-Fen | Juenemann, Katrin | Juhász, Gábor | Jung, Hye Seung | Jung, Jae U | Jung, Yong-Keun | Jungbluth, Heinz | Justice, Matthew J | Jutten, Barry | Kaakoush, Nadeem O | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kaeffer, Bertrand | Kågedal, Katarina | Kahana, Alon | Kajimura, Shingo | Kakhlon, Or | Kalia, Manjula | Kalvakolanu, Dhan V | Kamada, Yoshiaki | Kambas, Konstantinos | Kaminskyy, Vitaliy O | Kampinga, Harm H | Kandouz, Mustapha | Kang, Chanhee | Kang, Rui | Kang, Tae-Cheon | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G | Kantorow, Marc | Kaparakis-Liaskos, Maria | Kapuy, Orsolya | Karantza, Vassiliki | Karim, Md Razaul | Karmakar, Parimal | Kaser, Arthur | Kaushik, Susmita | Kawula, Thomas | Kaynar, A Murat | Ke, Po-Yuan | Ke, Zun-Ji | Kehrl, John H | Keller, Kate E | Kemper, Jongsook Kim
Autophagy  2016;12(1):1-222.
doi:10.1080/15548627.2015.1100356
PMCID: PMC4835977  PMID: 26799652
autolysosome; autophagosome; chaperone-mediated autophagy; flux; LC3; lysosome; macroautophagy; phagophore; stress; vacuole
2.  Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4+ T Lymphocytes 
Journal of Virology  2014;89(1):615-625.
ABSTRACT
Autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. Autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. Upon human immunodeficiency virus type 1 (HIV-1) infection, viral envelope (Env) glycoproteins induce autophagy-dependent apoptosis of uninfected bystander CD4+ T lymphocytes, a mechanism likely contributing to the loss of CD4+ T cells. In contrast, in productively infected CD4+ T cells, HIV-1 is able to block Env-induced autophagy in order to avoid its antiviral effect. To date, nothing is known about how autophagy restricts HIV-1 infection in CD4+ T lymphocytes. Here, we report that autophagy selectively degrades the HIV-1 transactivator Tat, a protein essential for viral transcription and virion production. We demonstrated that this selective autophagy-mediated degradation of Tat relies on its ubiquitin-independent interaction with the p62/SQSTM1 adaptor. Taken together, our results provide evidence that the anti-HIV effect of autophagy is specifically due to the degradation of the viral transactivator Tat but that this process is rapidly counteracted by the virus to favor its replication and spread.
IMPORTANCE Autophagy is recognized as one of the most ancient and conserved mechanisms of cellular defense against invading pathogens. Cross talk between HIV-1 and autophagy has been demonstrated depending on the virally challenged cell type, and HIV-1 has evolved strategies to block this process to replicate efficiently. However, the mechanisms by which autophagy restricts HIV-1 infection remain to be elucidated. Here, we report that the HIV-1 transactivator Tat, a protein essential for viral replication, is specifically degraded by autophagy in CD4+ T lymphocytes. Both Tat present in infected cells and incoming Tat secreted from infected cells are targeted for autophagy degradation through a ubiquitin-independent interaction with the autophagy receptor p62/SQSTM1. This study is the first to demonstrate that selective autophagy can be an antiviral process by degrading a viral transactivator. In addition, the results could help in the design of new therapies against HIV-1 by specifically targeting this mechanism.
doi:10.1128/JVI.02174-14
PMCID: PMC4301118  PMID: 25339774
3.  The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation 
Retrovirology  2015;12:53.
Background
Human immunodeficiency virus type 1 (HIV-1) has evolved a complex strategy to overcome the immune barriers it encounters throughout an organism thanks to its viral infectivity factor (Vif), a key protein for HIV-1 infectivity and in vivo pathogenesis. Vif interacts with and promotes “apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3G” (A3G) ubiquitination and subsequent degradation by the proteasome, thus eluding A3G restriction activity against HIV-1.
Results
We found that cellular histone deacetylase 6 (HDAC6) directly interacts with A3G through its C-terminal BUZ domain (residues 841–1,215) to undergo a cellular co-distribution along microtubules and cytoplasm. The HDAC6/A3G complex occurs in the absence or presence of Vif, competes for Vif-mediated A3G degradation, and accounts for A3G steady-state expression level. In fact, HDAC6 directly interacts with and promotes Vif autophagic clearance, thanks to its C-terminal BUZ domain, a process requiring the deacetylase activity of HDAC6. HDAC6 degrades Vif without affecting the core binding factor β (CBF-β), a Vif-associated partner reported to be key for Vif- mediated A3G degradation. Thus HDAC6 antagonizes the proviral activity of Vif/CBF-β-associated complex by targeting Vif and stabilizing A3G. Finally, in cells producing virions, we observed a clear-cut correlation between the ability of HDAC6 to degrade Vif and to restore A3G expression, suggesting that HDAC6 controls the amount of Vif incorporated into nascent virions and the ability of HIV-1 particles of being infectious. This effect seems independent on the presence of A3G inside virions and on viral tropism.
Conclusions
Our study identifies for the first time a new cellular complex, HDAC6/A3G, involved in the autophagic degradation of Vif, and suggests that HDAC6 represents a new antiviral factor capable of controlling HIV-1 infectiveness by counteracting Vif and its functions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-015-0181-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12977-015-0181-5
PMCID: PMC4479245  PMID: 26105074
HIV-1; HDAC6; APOBEC3G; Vif; CBF-β; Anti-HIV-1 restriction complex; Autophagic clearance
4.  Guidelines for the use and interpretation of assays for monitoring autophagy 
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Tony | Ekmekcioglu, Suhendan | El-Deiry, Wafik S. | Elazar, Zvulun | Elgendy, Mohamed | Ellerby, Lisa M. | Eng, Kai Er | Engelbrecht, Anna-Mart | Engelender, Simone | Erenpreisa, Jekaterina | Escalante, Ricardo | Esclatine, Audrey | Eskelinen, Eeva-Liisa | Espert, Lucile | Espina, Virginia | Fan, Huizhou | Fan, Jia | Fan, Qi-Wen | Fan, Zhen | Fang, Shengyun | Fang, Yongqi | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Farre, Jean-Claude | Faure, Mathias | Fechheimer, Marcus | Feng, Carl G. | Feng, Jian | Feng, Qili | Feng, Youji | Fésüs, László | Feuer, Ralph | Figueiredo-Pereira, Maria E. | Fimia, Gian Maria | Fingar, Diane C. | Finkbeiner, Steven | Finkel, Toren | Finley, Kim D. | Fiorito, Filomena | Fisher, Edward A. | Fisher, Paul B. | Flajolet, Marc | Florez-McClure, Maria L. | Florio, Salvatore | Fon, Edward A. | Fornai, Francesco | Fortunato, Franco | Fotedar, Rati | Fowler, Daniel H. | Fox, Howard S. | Franco, Rodrigo | Frankel, Lisa B. | Fransen, Marc | Fuentes, José M. | Fueyo, Juan | Fujii, Jun | Fujisaki, Kozo | Fujita, Eriko | Fukuda, Mitsunori | Furukawa, Ruth H. | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galliot, Brigitte | Galy, Vincent | Ganesh, Subramaniam | Ganetzky, Barry | Ganley, Ian G. | Gao, Fen-Biao | Gao, George F. | Gao, Jinming | Garcia, Lorena | Garcia-Manero, Guillermo | Garcia-Marcos, Mikel | Garmyn, Marjan | Gartel, Andrei L. | Gatti, Evelina | Gautel, Mathias | Gawriluk, Thomas R. | Gegg, Matthew E. | Geng, Jiefei | Germain, Marc | Gestwicki, Jason E. | Gewirtz, David A. | Ghavami, Saeid | Ghosh, Pradipta | Giammarioli, Anna M. | Giatromanolaki, Alexandra N. | Gibson, Spencer B. | Gilkerson, Robert W. | Ginger, Michael L. | Ginsberg, Henry N. | Golab, Jakub | Goligorsky, Michael S. | Golstein, Pierre | Gomez-Manzano, Candelaria | Goncu, Ebru | Gongora, Céline | Gonzalez, Claudio D. | Gonzalez, Ramon | González-Estévez, Cristina | González-Polo, Rosa Ana | Gonzalez-Rey, Elena | Gorbunov, Nikolai V. | Gorski, Sharon | Goruppi, Sandro | Gottlieb, Roberta A. | Gozuacik, Devrim | Granato, Giovanna Elvira | Grant, Gary D. | Green, Kim N. | Gregorc, Ales | Gros, Frédéric | Grose, Charles | Grunt, Thomas W. | Gual, Philippe | Guan, Jun-Lin | Guan, Kun-Liang | Guichard, Sylvie M. | Gukovskaya, Anna S. | Gukovsky, Ilya | Gunst, Jan | Gustafsson, Åsa B. | Halayko, Andrew J. | Hale, Amber N. | Halonen, Sandra K. | Hamasaki, Maho | Han, Feng | Han, Ting | Hancock, Michael K. | Hansen, Malene | Harada, Hisashi | Harada, Masaru | Hardt, Stefan E. | Harper, J. Wade | Harris, Adrian L. | Harris, James | Harris, Steven D. | Hashimoto, Makoto | Haspel, Jeffrey A. | Hayashi, Shin-ichiro | Hazelhurst, Lori A. | He, Congcong | He, You-Wen | Hébert, Marie-Josée | Heidenreich, Kim A. | Helfrich, Miep H. | Helgason, Gudmundur V. | Henske, Elizabeth P. | Herman, Brian | Herman, Paul K. | Hetz, Claudio | Hilfiker, Sabine | Hill, Joseph A. | Hocking, Lynne J. | Hofman, Paul | Hofmann, Thomas G. | Höhfeld, Jörg | Holyoake, Tessa L. | Hong, Ming-Huang | Hood, David A. | Hotamisligil, Gökhan S. | Houwerzijl, Ewout J. | Høyer-Hansen, Maria | Hu, Bingren | Hu, Chien-an A. | Hu, Hong-Ming | Hua, Ya | Huang, Canhua | Huang, Ju | Huang, Shengbing | Huang, Wei-Pang | Huber, Tobias B. | Huh, Won-Ki | Hung, Tai-Ho | Hupp, Ted R. | Hur, Gang Min | Hurley, James B. | Hussain, Sabah N.A. | Hussey, Patrick J. | Hwang, Jung Jin | Hwang, Seungmin | Ichihara, Atsuhiro | Ilkhanizadeh, Shirin | Inoki, Ken | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L. | Ip, Nancy Y. | Isaka, Yoshitaka | Ishida, Hiroyuki | Isidoro, Ciro | Isobe, Ken-ichi | Iwasaki, Akiko | Izquierdo, Marta | Izumi, Yotaro | Jaakkola, Panu M. | Jäättelä, Marja | Jackson, George R. | Jackson, William T. | Janji, Bassam | Jendrach, Marina | Jeon, Ju-Hong | Jeung, Eui-Bae | Jiang, Hong | Jiang, Hongchi | Jiang, Jean X. | Jiang, Ming | Jiang, Qing | Jiang, Xuejun | Jiang, Xuejun | Jiménez, Alberto | Jin, Meiyan | Jin, Shengkan V. | Joe, Cheol O. | Johansen, Terje | Johnson, Daniel E. | Johnson, Gail V.W. | Jones, Nicola L. | Joseph, Bertrand | Joseph, Suresh K. | Joubert, Annie M. | Juhász, Gábor | Juillerat-Jeanneret, Lucienne | Jung, Chang Hwa | Jung, Yong-Keun | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kadowaki, Motoni | Kågedal, Katarina | Kamada, Yoshiaki | Kaminskyy, Vitaliy O. | Kampinga, Harm H. | Kanamori, Hiromitsu | Kang, Chanhee | Kang, Khong Bee | Kang, Kwang Il | Kang, Rui | Kang, Yoon-A | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G. | Kanthasamy, Arthi | Karantza, Vassiliki | Kaushal, Gur P. | Kaushik, Susmita | Kawazoe, Yoshinori | Ke, Po-Yuan | Kehrl, John H. | Kelekar, Ameeta | Kerkhoff, Claus | Kessel, David H. | Khalil, Hany | Kiel, Jan A.K.W. | Kiger, Amy A. | Kihara, Akio | Kim, Deok Ryong | Kim, Do-Hyung | Kim, Dong-Hou | Kim, Eun-Kyoung | Kim, Hyung-Ryong | Kim, Jae-Sung | Kim, Jeong Hun | Kim, Jin Cheon | Kim, John K. | Kim, Peter K. | Kim, Seong Who | Kim, Yong-Sun | Kim, Yonghyun | Kimchi, Adi | Kimmelman, Alec C. | King, Jason S. | Kinsella, Timothy J. | Kirkin, Vladimir | Kirshenbaum, Lorrie A. | Kitamoto, Katsuhiko | Kitazato, Kaio | Klein, Ludger | Klimecki, Walter T. | Klucken, Jochen | Knecht, Erwin | Ko, Ben C.B. | Koch, Jan C. | Koga, Hiroshi | Koh, Jae-Young | Koh, Young Ho | Koike, Masato | Komatsu, Masaaki | Kominami, Eiki | Kong, Hee Jeong | Kong, Wei-Jia | Korolchuk, Viktor I. | Kotake, Yaichiro | Koukourakis, Michael I. | Flores, Juan B. Kouri | Kovács, Attila L. | Kraft, Claudine | Krainc, Dimitri | Krämer, Helmut | Kretz-Remy, Carole | Krichevsky, Anna M. | Kroemer, Guido | Krüger, Rejko | Krut, Oleg | Ktistakis, Nicholas T. | Kuan, Chia-Yi | Kucharczyk, Roza | Kumar, Ashok | Kumar, Raj | Kumar, Sharad | Kundu, Mondira | Kung, Hsing-Jien | Kurz, Tino | Kwon, Ho Jeong | La Spada, Albert R. | Lafont, Frank | Lamark, Trond | Landry, Jacques | Lane, Jon D. | Lapaquette, Pierre | Laporte, Jocelyn F. | László, Lajos | Lavandero, Sergio | Lavoie, Josée N. | Layfield, Robert | Lazo, Pedro A. | Le, Weidong | Le Cam, Laurent | Ledbetter, Daniel J. | Lee, Alvin J.X. | Lee, Byung-Wan | Lee, Gyun Min | Lee, Jongdae | lee, Ju-hyun | Lee, Michael | Lee, Myung-Shik | Lee, Sug Hyung | Leeuwenburgh, Christiaan | Legembre, Patrick | Legouis, Renaud | Lehmann, Michael | Lei, Huan-Yao | Lei, Qun-Ying | Leib, David A. | Leiro, José | Lemasters, John J. | Lemoine, Antoinette | Lesniak, Maciej S. | Lev, Dina | Levenson, Victor V. | Levine, Beth | Levy, Efrat | Li, Faqiang | Li, Jun-Lin | Li, Lian | Li, Sheng | Li, Weijie | Li, Xue-Jun | Li, Yan-Bo | Li, Yi-Ping | Liang, Chengyu | Liang, Qiangrong | Liao, Yung-Feng | Liberski, Pawel P. | Lieberman, Andrew | Lim, Hyunjung J. | Lim, Kah-Leong | Lim, Kyu | Lin, Chiou-Feng | Lin, Fu-Cheng | Lin, Jian | Lin, Jiandie D. | Lin, Kui | Lin, Wan-Wan | Lin, Weei-Chin | Lin, Yi-Ling | Linden, Rafael | Lingor, Paul | Lippincott-Schwartz, Jennifer | Lisanti, Michael P. | Liton, Paloma B. | Liu, Bo | Liu, Chun-Feng | Liu, Kaiyu | Liu, Leyuan | Liu, Qiong A. | Liu, Wei | Liu, Young-Chau | Liu, Yule | Lockshin, Richard A. | Lok, Chun-Nam | Lonial, Sagar | Loos, Benjamin | Lopez-Berestein, Gabriel | López-Otín, Carlos | Lossi, Laura | Lotze, Michael T. | Low, Peter | Lu, Binfeng | Lu, Bingwei | Lu, Bo | Lu, Zhen | Luciano, Fréderic | Lukacs, Nicholas W. | Lund, Anders H. | Lynch-Day, Melinda A. | Ma, Yong | Macian, Fernando | MacKeigan, Jeff P. | Macleod, Kay F. | Madeo, Frank | Maiuri, Luigi | Maiuri, Maria Chiara | Malagoli, Davide | Malicdan, May Christine V. | Malorni, Walter | Man, Na | Mandelkow, Eva-Maria | Manon, Stephen | Manov, Irena | Mao, Kai | Mao, Xiang | Mao, Zixu | Marambaud, Philippe | Marazziti, Daniela | Marcel, Yves L. | Marchbank, Katie | Marchetti, Piero | Marciniak, Stefan J. | Marcondes, Mateus | Mardi, Mohsen | Marfe, Gabriella | Mariño, Guillermo | Markaki, Maria | Marten, Mark R. | Martin, Seamus J. | Martinand-Mari, Camille | Martinet, Wim | Martinez-Vicente, Marta | Masini, Matilde | Matarrese, Paola | Matsuo, Saburo | Matteoni, Raffaele | Mayer, Andreas | Mazure, Nathalie M. | McConkey, David J. | McConnell, Melanie J. | McDermott, Catherine | McDonald, Christine | McInerney, Gerald M. | McKenna, Sharon L. | McLaughlin, BethAnn | McLean, Pamela J. | McMaster, Christopher R. | McQuibban, G. Angus | Meijer, Alfred J. | Meisler, Miriam H. | Meléndez, Alicia | Melia, Thomas J. | Melino, Gerry | Mena, Maria A. | Menendez, Javier A. | Menna-Barreto, Rubem F. S. | Menon, Manoj B. | Menzies, Fiona M. | Mercer, Carol A. | Merighi, Adalberto | Merry, Diane E. | Meschini, Stefania | Meyer, Christian G. | Meyer, Thomas F. | Miao, Chao-Yu | Miao, Jun-Ying | Michels, Paul A.M. | Michiels, Carine | Mijaljica, Dalibor | Milojkovic, Ana | Minucci, Saverio | Miracco, Clelia | Miranti, Cindy K. | Mitroulis, Ioannis | Miyazawa, Keisuke | Mizushima, Noboru | Mograbi, Baharia | Mohseni, Simin | Molero, Xavier | Mollereau, Bertrand | Mollinedo, Faustino | Momoi, Takashi | Monastyrska, Iryna | Monick, Martha M. | Monteiro, Mervyn J. | Moore, Michael N. | Mora, Rodrigo | Moreau, Kevin | Moreira, Paula I. | Moriyasu, Yuji | Moscat, Jorge | Mostowy, Serge | Mottram, Jeremy C. | Motyl, Tomasz | Moussa, Charbel E.-H. | Müller, Sylke | Muller, Sylviane | Münger, Karl | Münz, Christian | Murphy, Leon O. | Murphy, Maureen E. | Musarò, Antonio | Mysorekar, Indira | Nagata, Eiichiro | Nagata, Kazuhiro | Nahimana, Aimable | Nair, Usha | Nakagawa, Toshiyuki | Nakahira, Kiichi | Nakano, Hiroyasu | Nakatogawa, Hitoshi | Nanjundan, Meera | Naqvi, Naweed I. | Narendra, Derek P. | Narita, Masashi | Navarro, Miguel | Nawrocki, Steffan T. | Nazarko, Taras Y. | Nemchenko, Andriy | Netea, Mihai G. | Neufeld, Thomas P. | Ney, Paul A. | Nezis, Ioannis P. | Nguyen, Huu Phuc | Nie, Daotai | Nishino, Ichizo | Nislow, Corey | Nixon, Ralph A. | Noda, Takeshi | Noegel, Angelika A. | Nogalska, Anna | Noguchi, Satoru | Notterpek, Lucia | Novak, Ivana | Nozaki, Tomoyoshi | Nukina, Nobuyuki | Nürnberger, Thorsten | Nyfeler, Beat | Obara, Keisuke | Oberley, Terry D. | Oddo, Salvatore | Ogawa, Michinaga | Ohashi, Toya | Okamoto, Koji | Oleinick, Nancy L. | Oliver, F. Javier | Olsen, Laura J. | Olsson, Stefan | Opota, Onya | Osborne, Timothy F. | Ostrander, Gary K. | Otsu, Kinya | Ou, Jing-hsiung James | Ouimet, Mireille | Overholtzer, Michael | Ozpolat, Bulent | Paganetti, Paolo | Pagnini, Ugo | Pallet, Nicolas | Palmer, Glen E. | Palumbo, Camilla | Pan, Tianhong | Panaretakis, Theocharis | Pandey, Udai Bhan | Papackova, Zuzana | Papassideri, Issidora | Paris, Irmgard | Park, Junsoo | Park, Ohkmae K. | Parys, Jan B. | Parzych, Katherine R. | Patschan, Susann | Patterson, Cam | Pattingre, Sophie | Pawelek, John M. | Peng, Jianxin | Perlmutter, David H. | Perrotta, Ida | Perry, George | Pervaiz, Shazib | Peter, Matthias | Peters, Godefridus J. | Petersen, Morten | Petrovski, Goran | Phang, James M. | Piacentini, Mauro | Pierre, Philippe | Pierrefite-Carle, Valérie | Pierron, Gérard | Pinkas-Kramarski, Ronit | Piras, Antonio | Piri, Natik | Platanias, Leonidas C. | Pöggeler, Stefanie | Poirot, Marc | Poletti, Angelo | Poüs, Christian | Pozuelo-Rubio, Mercedes | Prætorius-Ibba, Mette | Prasad, Anil | Prescott, Mark | Priault, Muriel | Produit-Zengaffinen, Nathalie | Progulske-Fox, Ann | Proikas-Cezanne, Tassula | Przedborski, Serge | Przyklenk, Karin | Puertollano, Rosa | Puyal, Julien | Qian, Shu-Bing | Qin, Liang | Qin, Zheng-Hong | Quaggin, Susan E. | Raben, Nina | Rabinowich, Hannah | Rabkin, Simon W. | Rahman, Irfan | Rami, Abdelhaq | Ramm, Georg | Randall, Glenn | Randow, Felix | Rao, V. Ashutosh | Rathmell, Jeffrey C. | Ravikumar, Brinda | Ray, Swapan K. | Reed, Bruce H. | Reed, John C. | Reggiori, Fulvio | Régnier-Vigouroux, Anne | Reichert, Andreas S. | Reiners, John J. | Reiter, Russel J. | Ren, Jun | Revuelta, José L. | Rhodes, Christopher J. | Ritis, Konstantinos | Rizzo, Elizete | Robbins, Jeffrey | Roberge, Michel | Roca, Hernan | Roccheri, Maria C. | Rocchi, Stephane | Rodemann, H. Peter | Rodríguez de Córdoba, Santiago | Rohrer, Bärbel | Roninson, Igor B. | Rosen, Kirill | Rost-Roszkowska, Magdalena M. | Rouis, Mustapha | Rouschop, Kasper M.A. | Rovetta, Francesca | Rubin, Brian P. | Rubinsztein, David C. | Ruckdeschel, Klaus | Rucker, Edmund B. | Rudich, Assaf | Rudolf, Emil | Ruiz-Opazo, Nelson | Russo, Rossella | Rusten, Tor Erik | Ryan, Kevin M. | Ryter, Stefan W. | Sabatini, David M. | Sadoshima, Junichi | Saha, Tapas | Saitoh, Tatsuya | Sakagami, Hiroshi | Sakai, Yasuyoshi | Salekdeh, Ghasem Hoseini | Salomoni, Paolo | Salvaterra, Paul M. | Salvesen, Guy | Salvioli, Rosa | Sanchez, Anthony M.J. | Sánchez-Alcázar, José A. | Sánchez-Prieto, Ricardo | Sandri, Marco | Sankar, Uma | Sansanwal, Poonam | Santambrogio, Laura | Saran, Shweta | Sarkar, Sovan | Sarwal, Minnie | Sasakawa, Chihiro | Sasnauskiene, Ausra | Sass, Miklós | Sato, Ken | Sato, Miyuki | Schapira, Anthony H.V. | Scharl, Michael | Schätzl, Hermann M. | Scheper, Wiep | Schiaffino, Stefano | Schneider, Claudio | Schneider, Marion E. | Schneider-Stock, Regine | Schoenlein, Patricia V. | Schorderet, Daniel F. | Schüller, Christoph | Schwartz, Gary K. | Scorrano, Luca | Sealy, Linda | Seglen, Per O. | Segura-Aguilar, Juan | Seiliez, Iban | Seleverstov, Oleksandr | Sell, Christian | Seo, Jong Bok | Separovic, Duska | Setaluri, Vijayasaradhi | Setoguchi, Takao | Settembre, Carmine | Shacka, John J. | Shanmugam, Mala | Shapiro, Irving M. | Shaulian, Eitan | Shaw, Reuben J. | Shelhamer, James H. | Shen, Han-Ming | Shen, Wei-Chiang
Autophagy  2012;8(4):445-544.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
doi:10.4161/auto.19496
PMCID: PMC3404883  PMID: 22966490
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
5.  Inhibition of HIV-1 replication with stable RNAi-mediated knockdown of autophagy factors 
Virology Journal  2012;9:69.
Autophagy is a cellular process leading to the degradation of cytoplasmic components such as organelles and intracellular pathogens. It has been shown that HIV-1 relies on several components of the autophagy pathway for its replication, but the virus also blocks late steps of autophagy to prevent its degradation. We generated stable knockdown T cell lines for 12 autophagy factors and analyzed the impact on HIV-1 replication. RNAi-mediated knockdown of 5 autophagy factors resulted in inhibition of HIV-1 replication. Autophagy analysis confirmed a specific defect in the autophagy pathway for 4 of these 5 factors. We also scored the impact on cell viability, but no gross effects were observed. Upon simultaneous knockdown of 2 autophagy factors (Atg16 and Atg5), an additive inhibitory effect was scored on HIV-1 replication. Stable knockdown of several autophagy factors inhibit HIV-1 replication without any apparent cytotoxicity. We therefore propose that targeting of the autophagy pathway can be a novel therapeutic approach against HIV-1
doi:10.1186/1743-422X-9-69
PMCID: PMC3342116  PMID: 22424437
HIV-1; Autophagy; RNAi; Antiviral
6.  Macroautophagy Regulation during HIV-1 Infection of CD4+ T Cells and Macrophages 
Autophagy is an intracellular mechanism whereby pathogens, particularly viruses, are destroyed in autolysosomes after their entry into targets cells. Therefore, to survive and replicate in host cells, viruses have developed multiple strategies to either counteract or exploit this process. The aim of this review is to outline the known relationships between HIV-1 and autophagy in CD4+ T lymphocytes and macrophages, two main HIV-1 cell targets. The differential regulation of autophagy in these two cell-types is highlighted and its potential consequences in terms of viral replication and physiopathology discussed.
doi:10.3389/fimmu.2012.00097
PMCID: PMC3345938  PMID: 22586428
autophagy; HIV-1; CD4+ T cells; macrophages; infection
7.  IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network 
PLoS Pathogens  2011;7(12):e1002422.
Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity.
Author Summary
Autophagy is a highly regulated cellular degradative pathway for recycling of long-lived proteins and damaged organelles. Autophagy is also used by host cells as a defense mechanism against intracellular pathogens. Autophagy can degrade pathogens or pathogen-derived molecules trapped within specialized vesicles named autophagosomes. Viruses and viral proteins are not an exception. However, since autophagy is a conserved pathway, viruses were submitted to an evolutionary pressure that led to the selection of molecular strategies which avoid or subvert this process to promote viral replication. Nevertheless the molecular details of viral interaction with autophagy remain largely unknown. We determined the ability of 83 proteins of several families of RNA viruses (including Hepatitis C virus (HCV), human immunodeficiency virus 1 (HIV-1), Measles virus (MeV) and influenza A virus) to interact with 44 human proteins known to regulate autophagy and found that autophagy is highly targeted by RNA viruses. Strikingly, immunity-associated GTPase family M (IRGM), known for its role in autophagy against bacteria, is the most targeted autophagy protein. Its absence is detrimental for HCV, HIV-1 and MeV production. Therefore, our data show that different RNA viruses families use similar strategies to fine tune autophagy to their own benefit.
doi:10.1371/journal.ppat.1002422
PMCID: PMC3234227  PMID: 22174682
8.  Differential Role of Autophagy in CD4 T Cells and Macrophages during X4 and R5 HIV-1 Infection 
PLoS ONE  2009;4(6):e5787.
Background
HIV-1 can infect and replicate in both CD4 T cells and macrophages. In these cell types, HIV-1 entry is mediated by the binding of envelope glycoproteins (gp120 and gp41, Env) to the receptor CD4 and a coreceptor, principally CCR5 or CXCR4, depending on the viral strain (R5 or X4, respectively). Uninfected CD4 T cells undergo X4 Env-mediated autophagy, leading to their apoptosis, a mechanism now recognized as central to immunodeficiency.
Methodology/Principal Findings
We demonstrate here that autophagy and cell death are also induced in the uninfected CD4 T cells by HIV-1 R5 Env, while autophagy is inhibited in productively X4 or R5-infected CD4 T cells. In contrast, uninfected macrophages, a preserved cell population during HIV-1 infection, do not undergo X4 or R5 Env-mediated autophagy. Autophagosomes, however, are present in macrophages exposed to infectious HIV-1 particles, independently of coreceptor use. Interestingly, we observed two populations of autophagic cells: one highly autophagic and the other weakly autophagic. Surprisingly, viruses could be detected in the weakly autophagic cells but not in the highly autophagic cells. In addition, we show that the triggering of autophagy in macrophages is necessary for viral replication but addition of Bafilomycin A1, which blocks the final stages of autophagy, strongly increases productive infection.
Conclusions/Significance
Taken together, our data suggest that autophagy plays a complex, but essential, role in HIV pathology by regulating both viral replication and the fate of the target cells.
doi:10.1371/journal.pone.0005787
PMCID: PMC2686268  PMID: 19492063
9.  Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes 
Klionsky, Daniel J. | Abeliovich, Hagai | Agostinis, Patrizia | Agrawal, Devendra K. | Aliev, Gjumrakch | Askew, David S. | Baba, Misuzu | Baehrecke, Eric H. | Bahr, Ben A. | Ballabio, Andrea | Bamber, Bruce A. | Bassham, Diane C. | Bergamini, Ettore | Bi, Xiaoning | Biard-Piechaczyk, Martine | Blum, Janice S. | Bredesen, Dale E. | Brodsky, Jeffrey L. | Brumell, John H. | Brunk, Ulf T. | Bursch, Wilfried | Camougrand, Nadine | Cebollero, Eduardo | Cecconi, Francesco | Chen, Yingyu | Chin, Lih-Shen | Choi, Augustine | Chu, Charleen T. | Chung, Jongkyeong | Clarke, Peter G.H. | Clark, Robert S.B. | Clarke, Steven G. | Clavé, Corinne | Cleveland, John L. | Codogno, Patrice | Colombo, María I. | Coto-Montes, Ana | Cregg, James M. | Cuervo, Ana Maria | Debnath, Jayanta | Demarchi, Francesca | Dennis, Patrick B. | Dennis, Phillip A. | Deretic, Vojo | Devenish, Rodney J. | Di Sano, Federica | Dice, J. Fred | DiFiglia, Marian | Dinesh-Kumar, Savithramma | Distelhorst, Clark W. | Djavaheri-Mergny, Mojgan | Dorsey, Frank C. | Dröge, Wulf | Dron, Michel | Dunn, William A. | Duszenko, Michael | Eissa, N. Tony | Elazar, Zvulun | Esclatine, Audrey | Eskelinen, Eeva-Liisa | Fésüs, László | Finley, Kim D. | Fuentes, José M. | Fueyo, Juan | Fujisaki, Kozo | Galliot, Brigitte | Gao, Fen-Biao | Gewirtz, David A. | Gibson, Spencer B. | Gohla, Antje | Goldberg, Alfred L. | Gonzalez, Ramon | González-Estévez, Cristina | Gorski, Sharon | Gottlieb, Roberta A. | Häussinger, Dieter | He, You-Wen | Heidenreich, Kim | Hill, Joseph A. | Høyer-Hansen, Maria | Hu, Xun | Huang, Wei-Pang | Iwasaki, Akiko | Jäättelä, Marja | Jackson, William T. | Jiang, Xuejun | Jin, Shengkan | Johansen, Terje | Jung, Jae U. | Kadowaki, Motoni | Kang, Chanhee | Kelekar, Ameeta | Kessel, David H. | Kiel, Jan A.K.W. | Kim, Hong Pyo | Kimchi, Adi | Kinsella, Timothy J. | Kiselyov, Kirill | Kitamoto, Katsuhiko | Knecht, Erwin | Komatsu, Masaaki | Kominami, Eiki | Kondo, Seiji | Kovács, Attila L. | Kroemer, Guido | Kuan, Chia-Yi | Kumar, Rakesh | Kundu, Mondira | Landry, Jacques | Laporte, Marianne | Le, Weidong | Lei, Huan-Yao | Lenardo, Michael J. | Levine, Beth | Lieberman, Andrew | Lim, Kah-Leong | Lin, Fu-Cheng | Liou, Willisa | Liu, Leroy F. | Lopez-Berestein, Gabriel | López-Otín, Carlos | Lu, Bo | Macleod, Kay F. | Malorni, Walter | Martinet, Wim | Matsuoka, Ken | Mautner, Josef | Meijer, Alfred J. | Meléndez, Alicia | Michels, Paul | Miotto, Giovanni | Mistiaen, Wilhelm P. | Mizushima, Noboru | Mograbi, Baharia | Monastyrska, Iryna | Moore, Michael N. | Moreira, Paula I. | Moriyasu, Yuji | Motyl, Tomasz | Münz, Christian | Murphy, Leon O. | Naqvi, Naweed I. | Neufeld, Thomas P. | Nishino, Ichizo | Nixon, Ralph A. | Noda, Takeshi | Nürnberg, Bernd | Ogawa, Michinaga | Oleinick, Nancy L. | Olsen, Laura J. | Ozpolat, Bulent | Paglin, Shoshana | Palmer, Glen E. | Papassideri, Issidora | Parkes, Miles | Perlmutter, David H. | Perry, George | Piacentini, Mauro | Pinkas-Kramarski, Ronit | Prescott, Mark | Proikas-Cezanne, Tassula | Raben, Nina | Rami, Abdelhaq | Reggiori, Fulvio | Rohrer, Bärbel | Rubinsztein, David C. | Ryan, Kevin M. | Sadoshima, Junichi | Sakagami, Hiroshi | Sakai, Yasuyoshi | Sandri, Marco | Sasakawa, Chihiro | Sass, Miklós | Schneider, Claudio | Seglen, Per O. | Seleverstov, Oleksandr | Settleman, Jeffrey | Shacka, John J. | Shapiro, Irving M. | Sibirny, Andrei | Silva-Zacarin, Elaine C.M. | Simon, Hans-Uwe | Simone, Cristiano | Simonsen, Anne | Smith, Mark A. | Spanel-Borowski, Katharina | Srinivas, Vickram | Steeves, Meredith | Stenmark, Harald | Stromhaug, Per E. | Subauste, Carlos S. | Sugimoto, Seiichiro | Sulzer, David | Suzuki, Toshihiko | Swanson, Michele S. | Tabas, Ira | Takeshita, Fumihiko | Talbot, Nicholas J. | Tallóczy, Zsolt | Tanaka, Keiji | Tanaka, Kozo | Tanida, Isei | Taylor, Graham S. | Taylor, J. Paul | Terman, Alexei | Tettamanti, Gianluca | Thompson, Craig B. | Thumm, Michael | Tolkovsky, Aviva M. | Tooze, Sharon A. | Truant, Ray | Tumanovska, Lesya V. | Uchiyama, Yasuo | Ueno, Takashi | Uzcátegui, Néstor L. | van der Klei, Ida | Vaquero, Eva C. | Vellai, Tibor | Vogel, Michael W. | Wang, Hong-Gang | Webster, Paul | Wiley, John W. | Xi, Zhijun | Xiao, Gutian | Yahalom, Joachim | Yang, Jin-Ming | Yap, George | Yin, Xiao-Ming | Yoshimori, Tamotsu | Yu, Li | Yue, Zhenyu | Yuzaki, Michisuke | Zabirnyk, Olga | Zheng, Xiaoxiang | Zhu, Xiongwei | Deter, Russell L.
Autophagy  2007;4(2):151-175.
Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
PMCID: PMC2654259  PMID: 18188003
autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
10.  Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4 
The Journal of Clinical Investigation  2006;116(8):2161-2172.
HIV-1 envelope glycoproteins (Env), expressed at the cell surface, induce apoptosis of uninfected CD4+ T cells, contributing to the development of AIDS. Here we demonstrate that, independently of HIV replication, transfected or HIV-infected cells that express Env induced autophagy and accumulation of Beclin 1 in uninfected CD4+ T lymphocytes via CXCR4. The same phenomena occurred in a T cell line and in transfected HEK.293 cells that expressed both wild-type CXCR4 and a truncated form of CD4 that is unable to bind the lymphocyte-specific protein kinase Lck. Env-mediated autophagy is required to trigger CD4+ T cell apoptosis since blockade of autophagy at different steps, by either drugs (3-methyladenine and bafilomycin A1) or siRNAs specific for Beclin 1/Atg6 and Atg7 genes, totally inhibited the apoptotic process. Furthermore, CD4+ T cells still underwent Env-mediated cell death with autophagic features when apoptosis was inhibited. These results suggest that HIV-infected cells can induce autophagy in bystander CD4+ T lymphocytes through contact of Env with CXCR4, leading to apoptotic cell death, a mechanism most likely contributing to immunodeficiency.
doi:10.1172/JCI26185
PMCID: PMC1523410  PMID: 16886061
11.  Apoptosis of uninfected cells induced by HIV envelope glycoproteins 
Retrovirology  2004;1:12.
Apoptosis, or programmed cell death, is a key event in biologic homeostasis but is also involved in the pathogenesis of many human diseases including human immunodeficiency virus (HIV) infection. Although multiple mechanisms contribute to the gradual T cell decline that occurs in HIV-infected patients, programmed cell death of uninfected bystander T lymphocytes, including CD4+ and CD8+ T cells, is an important event leading to immunodeficiency. The HIV envelope glycoproteins (Env) play a crucial role in transducing this apoptotic signal after binding to its receptors, the CD4 molecule and a coreceptor, essentially CCR5 and CXCR4. Depending on Env presentation, the receptor involved and the complexity of target cell contact, apoptosis induction is related to death receptor and/or mitochondria-dependent pathways. This review summarizes current knowledge of Env-mediated cell death leading to T cell depletion and clinical complications and covers the sometimes conflicting studies that address the possible mechanisms of T cell death.
doi:10.1186/1742-4690-1-12
PMCID: PMC446229  PMID: 15214962
12.  The Complementary Strand of the Human T-Cell Leukemia Virus Type 1 RNA Genome Encodes a bZIP Transcription Factor That Down-Regulates Viral Transcription 
Journal of Virology  2002;76(24):12813-12822.
The RNA genome of the human T-cell leukemia virus type 1 (HTLV-1) codes for proteins involved in infectivity, replication, and transformation. We report in this study the characterization of a novel viral protein encoded by the complementary strand of the HTLV-1 RNA genome. This protein, designated HBZ (for HTLV-1 bZIP factor), contains a N-terminal transcriptional activation domain and a leucine zipper motif in its C terminus. We show here that HBZ is able to interact with the bZIP transcription factor CREB-2 (also called ATF-4), known to activate the HTLV-1 transcription by recruiting the viral trans-activator Tax on the Tax-responsive elements (TxREs). However, we demonstrate that the HBZ/CREB-2 heterodimers are no more able to bind to the TxRE and cyclic AMP response element sites. Taking these findings together, the functional inactivation of CREB-2 by HBZ is suggested to contribute to regulation of the HTLV-1 transcription. Moreover, the characterization of a minus-strand gene protein encoded by HTLV-1 has never been reported until now.
doi:10.1128/JVI.76.24.12813-12822.2002
PMCID: PMC136662  PMID: 12438606
13.  Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochrome c-Mediated Apoptosis Independently of Fas Signaling 
Journal of Virology  2001;75(16):7637-7650.
Apoptosis of CD4+ T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4+ T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4+ T-cell depletion in AIDS.
doi:10.1128/JVI.75.16.7637-7650.2001
PMCID: PMC114999  PMID: 11462036

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