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1.  Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy 
Autophagy  2012;8(9):1385-1386.
Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5S86A that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1K162,606R displays reduced kinase activity and fails to rescue autophagy in Ulk1−/− mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms.
PMCID: PMC3442885  PMID: 22717509
GSK3; Tip60; Ulk1; acetylation; autophagy; growth factor; phosphorylation
2.  The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy 
Autophagy  2012;8(4):690-691.
The fibroblast growth factor (FGF) signaling axis plays important roles in heart development. Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Using genetically engineered mouse and in vitro cultured embryoid body (EB) models, we demonstrate that FGF signaling suppresses premature differentiation of heart progenitor cells, as well as autophagy in outflow tract (OFT) myocardiac cells. The FGF also promotes mesoderm differentiation in embryonic stem cells (ESCs) but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, inhibition of FGF signaling increases myocardial differentiation and autophagy in both ex vivo cultured embryos and EBs, whereas activation of autophagy promotes myocardial differentiation. Thus, a link between FGF signals preventing premature differentiation of heart progenitor cells and suppression of autophagy has been established. These findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, and suggest a new venue to regulate stem/progenitor cell differentiation.
PMCID: PMC3405844  PMID: 22302007
FGF; autophagy; heart defect; heart development; premature differentiation; second heart field
3.  ATM Signals miRNA Biogenesis Through KSRP 
Molecular cell  2011;41(4):367-368.
In this issue of Molecular Cell, Zhang and colleagues describe a critical link between the DNA damage response and the miRNA pathway, in which DNA double strand breaks (DSBs) induce ATM-dependent KSRP phosphorylation to facilitate pri-miRNA processing.
PMCID: PMC3075113  PMID: 21329874
4.  Divalent regulation and intersubunit interactions of human Connexin26 (Cx26) hemichannels 
Channels  2013;8(1):1-4.
Control of plasma membrane connexin hemichannel opening is indispensable, and is achieved by physiological extracellular divalent ion concentrations. Here, we explore the differences between regulation by Ca2+ and Mg2+ of human connexin26 (hCx26) hemichannels and the role of a specific interaction in regulation by Ca2+. To effect hemichannel closure, the apparent affinity of Ca2+ (0.33 mM) is higher than for Mg2+ (1.8 mM). Hemichannel closure is accelerated by physiological Ca2+ concentrations, but non-physiological concentrations of extracellular Mg2+ are required for this effect. Our recent report provided evidence that extracellular Ca2+ facilitates hCx26 hemichannel closing by disrupting a salt bridge interaction between positions D50 and K61 that stabilizes the open state. New evidence from mutant cycle analysis indicates that D50 also interacts with Q48. We find that the D50-Q48 interaction contributes to stabilization of the open state, but that it is relatively insensitive to disruption by extracellular Ca2+ compared with the D50-K61 interaction.
PMCID: PMC4048337  PMID: 24126106
Connexin; gating; calcium; salt bridge; channelopathies
5.  A VISTA on PD-1H 
The Journal of Clinical Investigation  2014;124(5):1891-1893.
Three years ago, two research groups independently identified a previously undescribed T cell cosignaling molecule; one referred to it as V-domain Ig suppressor of T cell activation (VISTA), and the other used the term programmed death-1 homolog (PD-1H). Recombinant and ectopically expressed PD-1H functions as a coinhibitory ligand for T cell responses. However, the function of endogenous PD-1H is not clear. In this issue of the JCI, Flies and colleagues demonstrate that endogenous PD-1H on both T cells and APCs serves as a coinhibitory molecule for T cell activation and provide further support for targeting PD-1H as a therapeutic strategy for transplantation and cancers.
PMCID: PMC4001562  PMID: 24743142
7.  Mrap2 Accessory Linked to Obesity 
Cell metabolism  2013;18(3):309-311.
Melanocortin receptors are critical modulators of energy balance and glucose homeostasis. Companion studies published in Science (Asai et al., 2013; Sebag et al., 2013) establish a role for melanocortin receptor accessory protein 2 (Mrap2) in regulating melanocortin receptor activity and in the development of obesity in zebrafish, rodents, and humans.
PMCID: PMC3930449  PMID: 24011068
8.  Evolutionary flux of canonical microRNAs and mirtrons in Drosophila 
Nature genetics  2010;42(1):6-10.
Next-generation sequencing technologies generate vast catalogs of short RNA sequences from which to mine microRNAs. However, such data must be vetted to appropriately categorize microRNA precursors and interpret their evolution. A recent study annotated hundreds of microRNAs in three Drosophila species on the basis of singleton reads of heterogeneous length1. Our multi-million read datasets indicated that most of these were not substrates of RNAse III cleavage, and comprised many mRNA degradation fragments. We instead identified a distinct and smaller set of novel microRNAs supported by confident cloning signatures, including a high proportion of evolutionarily nascent mirtrons. Our data support a much lower rate in the emergence of lineage-specific microRNAs than previously inferred1, with a net flux of ~1 microRNA/million years of Drosophilid evolution.
PMCID: PMC4136759  PMID: 20037610
9.  Autophagic degradation of leaf starch in plants 
Autophagy  2013;9(8):1247-1248.
Autophagy is an evolutionarily conserved process in eukaryotic cells that functions to degrade cytoplasmic components in the vacuole or lysosome. Previous research indicates that the core molecular machinery of autophagosome formation works well in plants, and plant autophagy plays roles in diverse biological processes such as nutrient recycling, development, immunity and responses to a variety of abiotic stresses. Recently, we reported that autophagy contributed to leaf starch degradation, which had been thought to be a process confined to chloroplasts. This finding demonstrated a previously unidentified pathway of leaf starch depletion and a new role of basal autophagy in plants.
PMCID: PMC3748196  PMID: 23722252
autophagy; ATG; leaf starch degradation; SSGL; stromule
10.  Expanding the National Drug Abuse Treatment Clinical Trials Network to address the management of substance use disorders in general medical settings 
The Patient Protection and Affordable Care Act (2010) and the Mental Health Parity and Addiction Equity Act (2008) expand substance use disorder (SUD) care services in the USA into general medical settings. Care offered in these settings will engage substance-using patients in an integrated and patient-centered environment that addresses physical and mental health comorbidities and follows a chronic care model. This expansion of SUD services presents a great need for evidence-based practices useful in general medical settings, and reveals several research gaps to be addressed. The National Drug Abuse Treatment Clinical Trials Network of the National Institute on Drug Abuse can serve an important role in this endeavor. High-priority research gaps are highlighted in this commentary. A discussion follows on how the National Drug Abuse Treatment Clinical Trials Network can transform to address changing patterns in SUD care to efficiently generate evidence to guide SUD treatment practice within the context of recent US health care legislation.
PMCID: PMC4114899  PMID: 25114611
Patient Protection and Affordable Care Act; National Drug Abuse Treatment Clinical Trials Network; substance use disorders; practice-based research network; electronic health records
11.  Curbing the Use of Ultrasonography in the Diagnosis of Acute Kidney Injury 
Archives of internal medicine  2010;170(21):1907-1908.
PMCID: PMC4095784  PMID: 21098349
13.  Degradation of the endoplasmic reticulum by autophagy in plants 
Autophagy  2013;9(4):622-623.
Eukaryotic cells have developed sophisticated strategies to contend with environmental stresses faced in their lifetime. Endoplasmic reticulum (ER) stress occurs when the accumulation of unfolded proteins within the ER exceeds the folding capacity of ER chaperones. ER stress responses have been well characterized in animals and yeast, and autophagy has been suggested to play an important role in recovery from ER stress. In plants, the unfolded protein response signaling pathways have been studied, but changes in ER morphology and ER homeostasis during ER stress have not been analyzed previously. Autophagy has been reported to function in tolerance of several stress conditions in plants, including nutrient deprivation, salt and drought stresses, oxidative stress, and pathogen infection. However, whether autophagy also functions during ER stress has not been investigated. The goal of our study was to elucidate the role and regulation of autophagy during ER stress in Arabidopsis thaliana.
PMCID: PMC3627681  PMID: 23360963
endoplasmic reticulum; autophagy; Arabidopsis; IRE1; ER stress
14.  Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma 
Science translational medicine  2013;5(174):10.1126/scitranslmed.3004812.
Asthma is a prevalent disease of chronic inflammation in which endogenous counter-regulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 innate lymphoid cells (ILC2), can participate in the regulation of allergic airways responses, in particular airway mucosal inflammation. Here, we have identified both NK cells and ILC2 in human lung and peripheral blood in healthy and asthmatic subjects. NK cells were highly activated in severe asthma, linked to eosinophilia and interacted with autologous eosinophils to promote their apoptosis. ILC2 generated antigen-independent IL-13 in response to the mast cell product prostaglandin D2 (PGD2) alone and in a synergistic manner with the airway epithelial cytokines IL-25 and IL-33. Both NK cells and ILC2 expressed the pro-resolving ALX/FPR2 receptors. Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly increased NK cell mediated eosinophil apoptosis and decreased IL-13 release by ILC2. Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation. Because lipoxin A4 generation is decreased in severe asthma, these findings also implicate unrestrained ILC activation in asthma pathobiology.
PMCID: PMC3823369  PMID: 23447017
15.  Protective autophagy induced by RBX1/ROC1 knockdown or CRL inactivation via modulating the DEPTOR-MTOR axis 
Autophagy  2012;8(12):1856-1858.
RBX1/ROC1 is an essential subunit of the largest multiunit Cullin-RING E3 ligase (CRL), which controls the degradation of diverse substrates, thereby regulating numerous cellular processes. Recently, we reported that RBX1 is overexpressed in hepatocellular carcinomas (HCC) and its expression is negatively correlated with patient survival. Moreover, siRNA silencing of RBX1 inhibits the proliferation of liver cancer cells both in vitro and in vivo by inducing CDKN1A/p21-dependent cell senescence. Interestingly, independent of senescence, RBX1 knockdown also triggers an autophagy response, due, at least in part, to the accumulation of the MTOR-inhibitory protein DEPTOR, a recently identified CRL substrate. Biologically, blockage of autophagy significantly enhances the growth-suppressive effect of RBX1 knockdown by triggering massive apoptosis, indicating that the autophagy response upon RBX1 knockdown serves as a survival signal in liver cells. Similar observations were also made in many types of human cancer cells upon inhibition of CRL by MLN4924. These findings suggest that RBX1-CRL is a promising anti-cancer drug target and provide proof-of-concept evidence for a novel drug combination of RBX1-CRL inhibitor and autophagy inhibitor for effective treatment of human cancer.
PMCID: PMC3541304  PMID: 22965024
ROC1; RBX1; Cullin-RING E3 ligase; autophagy; senescence; DEPTOR; MTOR; neddylation; MLN4924
16.  Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells 
Autophagy  2012;8(11):1677-1679.
The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for the combination of MLN4924 with autophagy inhibitors to enhance therapeutic efficacy.
PMCID: PMC3494597  PMID: 22874562
Cullin-RING E3 ligase; SKP1-Cullin-F-box (SCF) E3 ligase; neddylation; NEDD8-activating enzyme; MLN4924; autophagy; DEPTOR; MTOR
17.  Does the Goldilocks Principle apply to calcium release restitution in heart cells? 
Journal of molecular and cellular cardiology  2011;52(1):10.1016/j.yjmcc.2011.10.014.
PMCID: PMC3814211  PMID: 22056316
18.  The bipolar–depressive continuum in the National Epidemiologic Survey on Alcohol and Related Conditions 
Bipolar disorders  2012;15(1):10.1111/bdi.12030.
PMCID: PMC3811045  PMID: 23231326
bipolar disorder; classification; depression
19.  When push comes to shove: SWI/SNF uses a nucleosome to get rid of a nucleosome 
Molecular cell  2010;38(4):484-486.
A report in this issue of Molecular Cell provides evidence that a translocating SWI/SNF-nucleosome complex efficiently displaces neighboring nucleosomes in vitro and may account for SWI/SNF-dependent nucleosome eviction in vivo.
PMCID: PMC3783944  PMID: 20513424
20.  Autophagy is impaired in cardiac ischemia-reperfusion injury 
Autophagy  2012;8(9):1394-1396.
Accumulating evidence attests to a prosurvival role for autophagy under stress, by facilitating removal of damaged proteins and organelles and recycling basic building blocks, which can be utilized for energy generation and targeted macromolecular synthesis to shore up cellular defenses. These observations are difficult to reconcile with the dichotomous prosurvival and death-inducing roles ascribed to macroautophagy in cardiac ischemia and reperfusion injury, respectively. A careful reexamination of ‘flux’ through the macroautophagy pathway reveals that autophagosome clearance is markedly impaired with reperfusion (reoxygenation) in cardiomyocytes following an ischemic (hypoxic) insult, resulting from reactive oxygen species (ROS)-mediated decline in LAMP2 and increase in BECN1 abundance. This results in impaired autophagy that is ‘ineffective’ in protecting against cell death with ischemia-reperfusion injury. Restoration of autophagosome clearance and by inference, ‘adequate’ autophagy, attenuates reoxygenation-induced cell death.
PMCID: PMC3442889  PMID: 22889942
BECN1; LAMP2; autophagic flux; cell death; ischemia-reperfusion; reactive oxygen species
21.  Proline dehydrogenase (oxidase), a mitochondrial tumor suppressor, and autophagy under the hypoxia microenvironment 
Autophagy  2012;8(9):1407-1409.
Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the pathway of proline catabolism, has been identified as a mitochondrial, metabolic tumor suppressor, which is downregulated in a variety of human tumors. However, our recent findings show that PRODH/POX is upregulated by hypoxia in vitro and in vivo. The combination of low glucose and hypoxia produces additive effects on PRODH/POX expression. Both hypoxia and glucose depletion enhance PRODH/POX expression through AMP-activated protein kinase (AMPK) activation to promote tumor cell survival. Nevertheless, the mechanisms underlying PRODH/POX prosurvival functions are different for hypoxia and low-glucose conditions. Glucose depletion with or without hypoxia elevates PRODH/POX and proline utilization to supply ATP for cellular energy needs. Interestingly, under hypoxia PRODH/POX induces protective autophagy by generating reactive oxygen species (ROS). AMPK is the main initiator of stress-triggered autophagy. Thus, PRODH/POX acts as a downstream effector of AMPK in the activation of autophagy under hypoxia. This regulation was confirmed to be independent of the mechanistic target of rapamycin (MTOR) pathway, a major downstream target of AMPK signaling.
PMCID: PMC3442893  PMID: 22885468
apoptosis; autophagy; hypoxia; metabolic stress; proline dehydrogenase/oxidase
22.  The Growing Array of Innate Inflammatory Ignition Switches in Osteoarthritis 
Arthritis and rheumatism  2012;64(7):2055-2058.
Osteoarthritis (OA) is the most common form of arthritis and is a major cause of chronic pain and disability. We currently lack disease-modifying OA medical therapeutics that effectively slow or halt the progression to destruction and failure of articular cartilage. Importantly, OA is a disease of the whole joint, including not only meniscal fibrocartilage and hyaline articular cartilage, but also subchondral bone, periarticular musculature, tendons and ligaments, articular adipose tissue, synovium, and synovial fluid (SF). Clinically, varying degrees of synovitis and joint effusion in OA contribute to signs and symptoms of inflammation (1). Multiple lines of evidence suggest that OA progression is promoted by low-grade innate articular inflammation and by synovitis (1,2). “Conventional” inflammatory cytokines expressed in cartilage and synovium likely play a role, and interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), IL-6, IL-8, and IL-17 are among the players in synovitis (1,2). The report by Nair et al in this issue of Arthritis & Rheumatism reveals increased levels of soluble CD14 (sCD14) in SF to be a biomarker of innate inflammation in patients undergoing arthroscopic knee meniscectomy for treatment of meniscal tears (3). Investigators in this group previously characterized this population as “enriched for patients with preradiographic disease” (4), given the associated symptoms, synovitis, and evidence of articular cartilage damage detected by arthroscopy.
PMCID: PMC3711830  PMID: 22488656
23.  Rap1 and its regulatory proteins 
Small GTPases  2012;3(3):192-197.
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, globally. Previously, we showed that Rap1GAP is a tumor suppressor gene that inhibits tumor growth, but promotes invasion in SCCHN. In this work, we discuss the role of Rap1 and Rap1GAP in SCCHN progression in the context of a microRNA-oncogene-tumor suppressor gene axis, and investigate the role of Rap1GAP in EZH2-mediated invasion. Loss of expression of microRNA-101 in SCCHN leads to upregulation of EZH2, a histone methyltransferase. Overexpression of EZH2 silences Rap1GAP via methylation, thereby promoting activation of its target, Rap1. This microRNA-controlled activation of Rap1, via EZH2-mediated silencing of Rap1GAP, is a novel mechanism of Rap1 regulation. In two independent SCCHN cell lines, downregulation of EZH2 inhibits proliferation and invasion. In both cell lines, stable knockdown of EZH2 (shEZH2) recovers Rap1GAP expression and inhibits proliferation. However, siRNA-mediated knockdown of Rap1GAP in these cells rescues proliferation but not invasion. Thus, EZH2 promotes proliferation and invasion via Rap1GAP-dependent and –independent mechanisms, respectively. Although the studies presented here are in the context of SCCHN, our results may have broader implications, given that Rap1GAP acts as a tumor suppressor in pancreatic cancer, thyroid cancer, and melanoma.
PMCID: PMC3442808  PMID: 22684501
EZH2; Rap1GAP; methylation; miR-101; translational
24.  E-box protein E2-2 is a crucial regulator of plasmacytoid DC development 
European journal of immunology  2008;38(9):2386-2388.
DC play central roles in priming both innate and adaptive immune responses. Multiple DC subsets have been identified on the basis of their phenotype and function. Plasmacytoid DC (pDC) are professional IFN-producing cells that play an essential role in anti-viral immunity. A series of recent studies demonstrates that the regulation of pDC development is different from other types of DC. In this issue of the European Journal of Immunology, new insight is provided into how human pDC development is regulated by various transcription factors, in particular by the Ets family protein Spi-B and E-box protein E2-2.
PMCID: PMC3652573  PMID: 18792016
DC; Developmental immunology; Transcription factors
25.  PI3K-Akt pathway regulates polycomb group protein and stem cell maintenance 
Cell Cycle  2013;12(2):199-200.
PMCID: PMC3575444  PMID: 23287474
PI3K; Akt; polycomb group protein; Bmi1; Ezh2; stem cell

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