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1.  EGFR-Mediated Phosphorylation of Beclin 1 in Autophagy Suppression, Tumor Progression and Tumor Chemoresistance 
Cell  2013;154(6):1269-1284.
Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic process including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds to the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated Class III phosphatidylinositol-3 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors, and restores autophagy in non-small cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance.
PMCID: PMC3917713  PMID: 24034250
2.  Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development 
Autophagy  2013;9(2):138-149.
Efficient apoptotic corpse clearance is essential for metazoan development and adult tissue homeostasis. Several autophagy proteins have been previously shown to function in apoptotic cell clearance; however, it remains unknown whether autophagy genes are essential for efficient apoptotic corpse clearance in the developing embryo. Here we show that, in Caenorhabditis elegans embryos, loss-of-function mutations in several autophagy genes that act at distinct steps in the autophagy pathway resulted in increased numbers of cell corpses and delayed cell corpse clearance. Further analysis of embryos with a null mutation in bec-1, the C. elegans ortholog of yeast VPS30/ATG6/mammalian beclin 1 (BECN1), revealed normal phosphatidylserine exposure on dying cells. Moreover, the corpse clearance defects of bec-1(ok691) embryos were rescued by BEC-1 expression in engulfing cells, and bec-1(ok691) enhanced corpse clearance defects in nematodes with simultaneous mutations in the engulfment genes, ced-1, ced-6 or ced-12. Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal.
PMCID: PMC3552879  PMID: 23108454
autophagy; apoptotic corpse clearance; C. elegans; embryogenesis; cell death
3.  Autophagy and Viruses: Adversaries or Allies? 
Journal of innate immunity  2013;5(5):480-493.
The autophagy pathway is an essential component of host defense against viral infection, orchestrating pathogen degradation (xenophagy), innate immune signaling, and certain aspects of adaptive immunity. Single autophagy proteins or cassettes of the core autophagy machinery can also function as antiviral factors independently of the canonical autophagy pathway. Moreover, to survive and propagate within the host, viruses have evolved a variety of strategies to evade autophagic attack and manipulate the autophagy machinery for their own benefit. This Review summarizes recent advances in understanding the antiviral and proviral roles of autophagy and previously unappreciated autophagy-independent functions of autophagy-related genes.
PMCID: PMC3790331  PMID: 23391695
Autophagy; virophagy; antiviral immunity
4.  Intestinal epithelial autophagy is essential for host defense against invasive bacteria 
Cell host & microbe  2013;13(6):723-734.
The mammalian intestine is colonized with a diverse community of bacteria that perform many beneficial functions but can threaten host health upon tissue invasion. Epithelial cell-intrinsic innate immune responses are essential to limit the invasion of both commensal and pathogenic bacteria and maintain beneficial host-bacterial relationships; however, little is known about the role of various cellular processes, notably autophagy, in controlling bacterial interactions with the intestinal epithelium in vivo. We demonstrate that intestinal epithelial cell autophagy protects against tissue invasion by both opportunistically invasive commensals and the invasive intestinal pathogen, Salmonella typhimurium. Autophagy is activated following bacterial invasion of epithelial cells through a process requiring epithelial cell-intrinsic signaling via the innate immune adaptor protein MyD88. Additionally, mice deficient in intestinal epithelial cell autophagy exhibit increased dissemination of invasive bacteria to extraintestinal sites. Thus, autophagy is an important epithelial cell-autonomous mechanism of antibacterial defense that protects against dissemination of intestinal bacteria.
PMCID: PMC3755484  PMID: 23768496
5.  Identification of a candidate therapeutic autophagy–inducing peptide 
Nature  2013;494(7436):201-206.
The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat–beclin 1—derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef—is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat–beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases.
PMCID: PMC3788641  PMID: 23364696
6.  The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis 
eLife  2013;2:e00947.
Autophagy is a catabolic process for bulk degradation of cytosolic materials mediated by double-membraned autophagosomes. The membrane determinant to initiate the formation of autophagosomes remains elusive. Here, we establish a cell-free assay based on LC3 lipidation to define the organelle membrane supporting early autophagosome formation. In vitro LC3 lipidation requires energy and is subject to regulation by the pathways modulating autophagy in vivo. We developed a systematic membrane isolation scheme to identify the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) as a primary membrane source both necessary and sufficient to trigger LC3 lipidation in vitro. Functional studies demonstrate that the ERGIC is required for autophagosome biogenesis in vivo. Moreover, we find that the ERGIC acts by recruiting the early autophagosome marker ATG14, a critical step for the generation of preautophagosomal membranes.
eLife digest
Cells continually adapt their behavior to accommodate changes in their environment. For example, when nutrients are abundant, cells can grow or proliferate; in times of scarcity, however, they must conserve resources for essential tasks. In particular, during periods of starvation, cells can cannibalize themselves in a process called autophagy, which literally means ‘self-eating’. Structures called autophagosomes engulf bits of cytoplasm and carry the contents to the digestive compartment of the cell, the lysosome, to be broken down into their constituent parts. This can include the degradation of proteins into amino acids, which can then be recycled into other proteins needed by the cell.
In cells, proteins are shipped to their destinations—which can be the plasma membrane or a specific organelle within the cell—via a delivery system known as the secretory pathway. This pathway begins in the endoplasmic reticulum (ER), where many of these proteins are made. From the ER, the proteins move to a compartment called the Golgi apparatus, which then sends them to their destinations, or to the lysosome to be broken down. Between the ER and Golgi they pass through a structure called the ER–Golgi intermediate compartment (ERGIC).
Although the signaling pathways that initiate autophagy are known, less is understood about the actual formation of the autophagosomes. Now, Ge et al. have developed an in vitro system to study their formation, and gone on to identify a membrane that is both necessary and sufficient to create these structures.
Previous studies have implicated a variety of membranes—including the plasma membrane and the membranes belonging to the ER, the Golgi apparatus, the lysosome and various other organelles—in the formation of autophagosomes. To identify which of these membranes might be involved, Ge et al. focused on a protein called LC3 that is a key marker for the formation of the autophagosome. This protein is recruited to the growing autophagosome by a lipid, so discovering which membranes can add a lipid to LC3 should shed light on the assembly process.
By separating the full range of organelles in a cell lysate into fractions (a process called fractionation), Ge et al. found that the ERGIC was the most active membrane to attach lipid to LC3. Additionally, the lipid was only added when signaling pathways that stimulate autophagy—such as the PI3K pathway—were activated. Together, these results provide insight into the mechanism of autophagosome formation, and the structures in the cell that participate in this process.
PMCID: PMC3736544  PMID: 23930225
autophagy; ER–Golgi intermediate compartment; LC3 lipidation; autophagosome; Human; Mouse
7.  Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes 
Nature immunology  2012;14(1):61-71.
Innate immune sensing of viral nucleic acids triggers type I interferon (IFN) production, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through IFN-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulates the activation of a subset of ISGs independently of IFN. Both Trex1−/− mouse and TREX1-mutant human cells express high levels of antiviral genes and are refractory to viral infections. The IFN-independent activation of antiviral genes in Trex1−/− cells requires STING, TBK1 and IRF3 and IRF7. We also found that Trex1-deficient cells display expanded lysosomal compartment, altered subcellular localization of the transcription factor EB (TFEB), and reduced mTORC1 activity. Together, our data identify Trex1 as a regulator of lysosomal biogenesis and IFN-independent activation of antiviral genes, and shows dysregulation of lysosomes can elicit innate immune responses.
PMCID: PMC3522772  PMID: 23160154
8.  A comprehensive glossary of autophagy-related molecules and processes 
Autophagy  2010;6(4):438-448.
Autophagy is a rapidly expanding field in the sense that our knowledge about the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. Similarly, the vocabulary associated with autophagy has grown concomitantly. This fact makes it difficult for readers, even those who work in the field, to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors or chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, or the role of accessory machinery or structures that are associated with autophagy.
PMCID: PMC3652604  PMID: 20484971
autophagy; definitions; glossary; lexicon; terms
9.  Autophagy modulation as a potential therapeutic target for diverse diseases 
Nature reviews. Drug discovery  2012;11(9):709-730.
Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.
PMCID: PMC3518431  PMID: 22935804
10.  Inheriting Maternal mtDNA 
Science (New York, N.Y.)  2011;334(6059):1069-1070.
PMCID: PMC3518432  PMID: 22116870
11.  Exercise–induced BCL2–regulated autophagy is required for muscle glucose homeostasis 
Nature  2012;481(7382):511-515.
Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes1. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control2. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism3. Moreover, in animal models, autophagy protects against diseases such as cancer, neuro-degenerative disorders, infections, inflammatory diseases, ageing and insulin resistance4-6. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)- induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
PMCID: PMC3518436  PMID: 22258505
12.  Snapshot of the network 
Nature  2010;466(7302):38-40.
Autophagy is an essential cellular process for protein and organelle quality control. Analyses of proteins that interact with the human autophagic machinery provide an outline of the molecular organization of this pathway.
PMCID: PMC3518437  PMID: 20596005
13.  Viral evasion of autophagy 
Autophagy  2007;4(3):280-285.
Autophagy is an evolutionarily ancient pathway for survival during different forms of cellular stress, including infection with viruses and other intracellular pathogens. Autophagy may protect against viral infection through degradation of viral components (xenophagy), by promoting the survival or death of infected cells, through delivery of Toll-like receptor (TLR) ligands to endosomes to activate innate immunity, or by feeding antigens to MHC class II compartments to activate adaptive immunity. Given this integral role of autophagy in innate and adaptive antiviral immunity, selective pressure likely promoted the emergence of escape mechanisms by pathogenic viruses. This review will briefly summarize the current understanding of autophagy as an antiviral pathway, and then discuss strategies that viruses may utilize to evade this host defense mechanism.
PMCID: PMC3508671  PMID: 18059171
autophagy; virus; xenophagy; immunity; viral evasion
14.  Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation 
Science (New York, N.Y.)  2012;338(6109):956-959.
Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
PMCID: PMC3507442  PMID: 23112296
15.  Ceramide-induced autophagy 
Autophagy  2009;5(4):558-560.
Ceramide is a sphingolipid bioactive molecule that induces apoptosis and other forms of cell death, and triggers macroautophagy (referred to below as autophagy). Like amino acid starvation, ceramide triggers autophagy by interfering with the mTOR-signaling pathway, and by dissociating the Beclin 1:Bcl-2 complex in a c-Jun N-terminal kinase 1 (JNK1)-mediated Bcl-2 phosphorylation-dependent manner. Dissociation of the Beclin 1:Bcl-2 complex, and the subsequent stimulation of autophagy have been observed in various contexts in which the cellular level of long-chain ceramides was increased. It is notable that the conversion of short-chain ceramides (C2-ceramide and C6-ceramide) into long-chain ceramide via the activity of ceramide synthase is required to trigger autophagy. The dissociation of the Beclin 1:Bcl-2 complex has also been observed in response to tamoxifen and PDMP (an inhibitor of the enzyme that converts ceramide to glucosylceramide), drugs that increase the intracellular level of long-chain ceramides. However, and in contrast to starvation, over-expression of Bcl-2 does not blunt ceramide-induced autophagy. Whether this autophagy that is unchecked by forced dissociation of the Beclin 1:Bcl-2 complex is related to the ability of ceramide to trigger cell death remains an open question. More generally, the question of whether ceramide-induced autophagy is a dedicated cell death mechanism deserves closer scrutiny.
PMCID: PMC3501009  PMID: 19337026
macroautophagy; Bcl-2; Beclin 1; c-Jun N-terminal kinase; cell death; sphingolipids
16.  Chikungunya virus–induced autophagy delays caspase-dependent cell death 
The Journal of Experimental Medicine  2012;209(5):1029-1047.
Chikungunya virus induces autophagy by triggering ER and oxidative stress, and this autophagy restricts apoptosis and viral propagation.
Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16LHM mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease.
PMCID: PMC3348111  PMID: 22508836
17.  A comprehensive glossary of autophagy-related molecules and processes (2nd edition) 
Autophagy  2011;7(11):1273-1294.
The study of autophagy is rapidly expanding, and our knowledge of the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. The vocabulary associated with autophagy has grown concomitantly. In fact, it is difficult for readers—even those who work in the field—to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors and chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, and the roles of accessory components and structures that are associated with autophagy.
PMCID: PMC3359482  PMID: 21997368
autophagy; lysosome; mitophagy; pexophagy; stress; vacuole
18.  Exercise induces autophagy in peripheral tissues and in the brain 
Autophagy  2012;8(10):1548-1551.
We recently identified physical exercise as a newly defined inducer of autophagy in vivo. Exercise induced autophagy in multiple organs involved in metabolic regulation, such as muscle, liver, pancreas and adipose tissue. To study the physiological role of exercise-induced autophagy, we generated mice with a knock-in nonphosphorylatable mutation in BCL2 (Thr69Ala, Ser70Ala and Ser84Ala) (BCL2 AAA) that are defective in exercise- and starvation-induced autophagy but not in basal autophagy. We found that BCL2 AAA mice could not run on a treadmill as long as wild-type mice, and did not undergo exercise-mediated increases in skeletal glucose muscle uptake. Unlike wild-type mice, the BCL2 AAA mice failed to reverse high-fat diet-induced glucose intolerance after 8 weeks of exercise training, possibly due to defects in signaling pathways that regulate muscle glucose uptake and metabolism during exercise. Together, these findings suggested a hitherto unknown important role of autophagy in mediating exercise-induced metabolic benefits. In the present addendum, we show that treadmill exercise also induces autophagy in the cerebral cortex of adult mice. This observation raises the intriguing question of whether autophagy may in part mediate the beneficial effects of exercise in neurodegeneration, adult neurogenesis and improved cognitive function.
PMCID: PMC3463459  PMID: 22892563
autophagy; exercise; brain; BCL2; metabolism
19.  Image-Based Genome-Wide siRNA Screen Identifies Selective Autophagy Factors 
Nature  2011;480(7375):113-117.
Selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction1–4. Yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy, and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation5. However, there have been no systematic approaches to identify molecular determinants of selective autophagy in mammalian cells. To identify mammalian genes required for selective autophagy, we performed a high-content, image-based, genome-wide siRNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. We identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to mRNA processing, interferon signaling, vesicle trafficking, cytoskeletal motor function, and metabolism. Ninety-six of these genes were also required for Parkin-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2-domain containing protein, Smurf1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, Smurf1-deficient mice display an accumulation of damaged mitochondria in heart, brain, and liver. Thus, our study identifies candidate determinants of selective autophagy, and defines Smurf1 as a newly recognized mediator of both viral autophagy and mitophagy.
PMCID: PMC3229641  PMID: 22020285
20.  RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly 
Cell  2011;144(2):253-267.
The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. We find that the Ras-like small G-protein, RalB, is localized to nascent autophagosomes and is activated upon nutrient deprivation. RalB and its effector Exo84 are required for nutrient starvation-induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery.
PMCID: PMC3038590  PMID: 21241894
21.  Calcipotriol Induces Autophagy in HeLa Cells and Keratinocytes 
PMCID: PMC3131686  PMID: 21228817
22.  Autophagy in immunity and inflammation 
Nature  2011;469(7330):323-335.
Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy — the ‘autophagy proteins’ — orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
PMCID: PMC3131688  PMID: 21248839
23.  Autophagy in mammalian development and differentiation 
Nature cell biology  2010;12(9):823-830.
It has been known for many decades that autophagy, a conserved lysosomal degradation pathway, is highly active during differentiation and development. However, until the discovery of the autophagy-related (ATG) genes in the 1990s, the functional significance of this activity was unknown. Initially, genetic knockout studies of ATG genes in lower eukaryotes revealed an essential role for the autophagy pathway in differentiation and development. In recent years, the analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation. Here we review the main advances in our understanding of these functions.
PMCID: PMC3127249  PMID: 20811354
24.  Autophagy and the integrated stress response 
Molecular cell  2010;40(2):280-293.
Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles or intracellular pathogens. Both specific, stimulus-dependent and more general stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multi-functional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response.
PMCID: PMC3127250  PMID: 20965422
25.  Autophagy and Innate Immunity: Triggering, Targeting and Tuning 
Autophagy is a conserved catabolic stress response pathway that is increasingly recognized as an important component of both innate and acquired immunity to pathogens. The activation of autophagy during infection not only provides cell-autonomous protection through lysosomal degradation of invading pathogens (xenophagy), but also regulates signaling by other innate immune pathways. This review will focus on recent advances in our understanding of three major areas of the interrelationship between autophagy and innate immunity, including how autophagy is triggered during infection, how invading pathogens are targeted to autophagosomes, and how the autophagy pathway participates in “tuning” the innate immune response.
PMCID: PMC2930105  PMID: 20403453

Results 1-25 (65)