Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology

Levine, Beth; Liu, Rong; Dong, Xiaonan; Zhong, Qing

doi:10.1016/j.tcb.2015.05.004

Cited by 145 publications

(146 citation statements)

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“…This direct effect of WASH on autophagosome formation is independent of its function as an NPF but seems to be mediated by inhibiting ubiquitylation of Beclin1/Atg6 (Xia et al, 2014). This tumor suppressor is part of a lipid kinase complex that mediates the initial stages of autophagosome biogenesis by recruiting other Atg proteins (Levine et al, 2015;Wirawan et al, 2012). However, Beclin1/Atg6 proteins are known to exert numerous non-autophagic functions, including protein sorting, and endocytic and phagosomal maturation (Levine et al, 2015;Wirawan et al, 2012).…”

Section: Research Articlementioning

confidence: 99%

“…This tumor suppressor is part of a lipid kinase complex that mediates the initial stages of autophagosome biogenesis by recruiting other Atg proteins (Levine et al, 2015;Wirawan et al, 2012). However, Beclin1/Atg6 proteins are known to exert numerous non-autophagic functions, including protein sorting, and endocytic and phagosomal maturation (Levine et al, 2015;Wirawan et al, 2012). In flies, Atg6 is also required for multiple vesicle trafficking pathways and hematopoiesis (Shravage et al, 2013).…”

Section: Research Articlementioning

confidence: 99%

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Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

Nagel

Bechtold

Rodríguez

et al. 2017

Journal of Cell Science

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The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH; also known as Washout in flies) is a conserved actin-nucleationpromoting factor controlling Arp2/3 complex activity in endosomal sorting and recycling. Previous studies have identified WASH as an essential regulator in Drosophila development. Here, we show that homozygous wash mutant flies are viable and fertile. We demonstrate that Drosophila WASH has conserved functions in integrin receptor recycling and lysosome neutralization. WASH generates actin patches on endosomes and lysosomes, thereby mediating both aforementioned functions. Consistently, loss of WASH function results in cell spreading and cell migration defects of macrophages, and an increased lysosomal acidification that affects efficient phagocytic and autophagic clearance. WASH physically interacts with the vacuolar (V)-ATPase subunit Vha55 that is crucial to establish and maintain lysosome acidification. As a consequence, starved flies that lack WASH function show a dramatic increase in acidic autolysosomes, causing a reduced lifespan. Thus, our data highlight a conserved role for WASH in the endocytic sorting and recycling of membrane proteins, such as integrins and the V-ATPase, that increase the likelihood of survival under nutrient deprivation.

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Section: Research Articlementioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

Nagel

Bechtold

Rodríguez

et al. 2017

Journal of Cell Science

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“…1 A and B), we asked whether the autophagy pathway and/or ATG proteins are involved in this response. Because Beclin 1 and PI3K were previously shown to be important in both the canonical (autophagosome nucleation and maturation) (25) and noncanonical (LAP) (20) autophagy pathways, we asked whether these proteins are needed in the IFN-γ-mediated restriction of liver-stage P. vivax. To answer this question, we used siRNA technology to knockdown Beclin 1 expression in HC04 cells.…”

Section: Ifn-γ-induced Protection Against Liver-stage P Vivax Dependmentioning

confidence: 99%

LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malariaPlasmodium vivaxliver stage

Boonhok

Rachaphaew

Duangmanee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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IFN-γ is a major regulator of immune functions and has been shown to induce liver-stage Plasmodium elimination both in vitro and in vivo. The molecular mechanism responsible for the restriction of liver-stage Plasmodium downstream of IFN-γ remains uncertain, however. Autophagy, a newly described immune defense mechanism, was recently identified as a downstream pathway activated in response to IFN-γ in the control of intracellular infections. We thus hypothesized that the killing of liver-stage malarial parasites by IFN-γ involves autophagy induction. Our results show that whereas IFN-γ treatment of human hepatocytes activates autophagy, the IFN-γ-mediated restriction of liver-stage Plasmodium vivax depends only on the downstream autophagy-related proteins Beclin 1, PI3K, and ATG5, but not on the upstream autophagy-initiating protein ULK1. In addition, IFN-γ enhanced the recruitment of LC3 onto the parasitophorous vacuole membrane (PVM) and increased the colocalization of lysosomal vesicles with P. vivax compartments. Taken together, these data indicate that IFN-γ mediates the control of liver-stage P. vivax by inducing a noncanonical autophagy pathway resembling that of LC3-associated phagocytosis, in which direct decoration of the PVM with LC3 promotes the fusion of P. vivax compartments with lysosomes and subsequent killing of the pathogen. Understanding the hepatocyte response to IFN-γ during Plasmodium infection and the roles of autophagy-related proteins may provide an urgently needed alternative strategy for the elimination of this human malaria.autophagy | LC3-associated phagocytosis | IFN-γ | malaria S everal hundred million cases of human malaria are reported annually, and nearly 600,000 people die from the disease each year (1). Of the five species that infect humans, Plasmodium vivax is not only the most geographically widespread, but also the most prevalent malarial parasite in areas outside Africa. As such, it has caused massive morbidity in these regions of the world. Although malaria caused by P. vivax was previously regarded as benign compared with that caused by Plasmodium falciparum, the recent alarming increase in both the severity and the drug resistance of P. vivax infection has raised concern (2).The widespread distribution of P. vivax has been attributed to the parasite's ability to remain dormant in the liver for years before reactivation (3). The molecular mechanism responsible for P. vivax dormancy is unknown, and knowledge of Plasmodiumhepatocyte interactions remains very limited. Nonetheless, because the number of liver-stage parasites is in the range of 100, whereas in the blood stage as many as 10 13 organisms may be found (4), intervention at the liver stage would seem to offer a better strategy for parasite elimination. A prerequisite to this route of malaria control and the development of novel therapies is a better understanding of liver-stage Plasmodium and its interactions with host hepatocytes. IFN-γ was previously shown to exhibit antimalarial activity against the liver stag...

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“…NRBF2 converts PI3KC3-C1 into a dimer, which changes how we think about the role of PI3KC3 in vesicle tethering. and fundamental role for this protein in autophagy (18). We set out to understand the role of NRBF2 in the assembly, activity, architecture, and dynamics of PI3KC3-C1.…”

mentioning

confidence: 99%

Dynamics and architecture of the NRBF2-containing phosphatidylinositol 3-kinase complex I of autophagy

Young

Cho

Lawrence

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) is central to autophagy initiation. We previously reported the V-shaped architecture of the four-subunit version of PI3KC3-C1 consisting of VPS (vacuolar protein sorting) 34, VPS15, BECN1 (Beclin 1), and ATG (autophagy-related) 14. Here we show that a putative fifth subunit, nuclear receptor binding factor 2 (NRBF2), is a tightly bound component of the complex that profoundly affects its activity and architecture. NRBF2 enhances the lipid kinase activity of the catalytic subunit, VPS34, by roughly 10-fold. We used hydrogen-deuterium exchange coupled to mass spectrometry and negative-stain electron microscopy to map NRBF2 to the base of the V-shaped complex. NRBF2 interacts primarily with the N termini of ATG14 and BECN1. We show that NRBF2 is a homodimer and drives the dimerization of the larger PI3KC3-C1 complex, with implications for the higherorder organization of the preautophagosomal structure.hydrogen-deuterium exchange | electron microscopy | allostery A utophagy is a pathway of subcellular engulfment and lysosomal transport that is conserved throughout eukaryotes (1). Survival during starvation is probably the primordial function of autophagy (2). Most current research focuses on a growing array of selective autophagy pathways in human cells (3). These include autophagy of mitochondria (mitophagy), endoplasmic reticulum (ER-phagy), and intracellular microbes (xenophagy). Autophagy is generally considered protective against a range of diseases, including several neurodegenerative diseases (4), microbial infections, and cancer (5). Autophagy can also promote tumor growth in late stages of cancer, and therefore agonists and antagonists of autophagy are of interest as potential therapeutics (5). The centrality of autophagy to both basic cell processes and human health has leant urgency to understanding its underlying molecular mechanisms.Bulk and selective autophagy share common machinery for the initiation and growth of the double-membrane sheet known as the phagophore. The phagophore matures and closes to form the autophagosome. The proteins dedicated to autophagy number ∼41 in yeast and more in humans. They include the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex [Atg1 (autophagy-related 1) complex in yeast], the phosphatidylinositol 3-kinase complexes I and II (PI3KC3-C1 and -C2), the integral membrane protein ATG9, the WIPIs as PI(3P) receptors, and the ubiquitin-like LC3 protein family and their conjugation pathway. PI3KC3-C1 functions in autophagy initiation (6, 7), whereas PI3KC3-C2 is important for autolysosome formation at a later step in autophagy (8). The two PI3KC3 complexes share three subunits in common: the lipid kinase subunit VPS34 (vacuolar protein sorting 34) and the regulatory subunits BECN1 (Beclin 1) and VPS15. PI3KC3-C2 contains the unique subunit UVRAG (UV radiation resistance associated), which is involved in regulating the fusion of autophagosomes to lysosomes (9). PI3KC3-C1 is targeted to ...

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Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology

Cited by 145 publications

References 155 publications

Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malariaPlasmodium vivaxliver stage

Dynamics and architecture of the NRBF2-containing phosphatidylinositol 3-kinase complex I of autophagy

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