The VMP1-Beclin 1 interaction regulates autophagy induction

Molejon, Maria Inés; Ropolo, Alejandro; Ré, Andrea Emilia Lo; Boggio, Verónica; Vaccaro, María I.

doi:10.1038/srep01055

Cited by 148 publications

(132 citation statements)

References 44 publications

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“…The synchronized recruitment of ATG5 with ULK1 might be mediated by a recently described interaction between the ULK complex subunit FIP200 and ATG16L1 (Gammoh et al, 2013;Nishimura et al, 2013). The VMP1-beclin 1 interaction was also found to facilitate the association of ATG16L1 and LC3 (also known as microtubule-associated protein 1 light chain 3) with the autophagosomal membranes (Molejon et al, 2013). As VMP1 expression is known to trigger autophagy (Ropolo et al, 2007) and because it seems to be the most 'temporally' upstream factor identified to date, it is tempting to hypothesize that VMP1 acts as a recruitment platform that determines the site of phagophore formation by recruitment of the early core ATG proteins.…”

Section: Phagophore Nucleationmentioning

confidence: 94%

“…ATG14L contains an ER-binding motif in its N-terminal domain, which appears to be essential for its function in autophagy and for the recruitment of the other PI3KC3 subunits (see Box 1) to the sites of phagophore formation ). An interaction between VMP1 and beclin 1 (Molejon et al, 2013) might further stabilize the association of the PI3KC3 complex with the ER membrane. Finally, the ATG12-ATG5-ATG16L1 complex (see Box 1) is recruited to the phagophore ( Fig.…”

Section: Phagophore Nucleationmentioning

confidence: 99%

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Membrane dynamics in autophagosome biogenesis

Carlsson

Simonsen

2015

Journal of Cell Science

188

169

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Bilayered phospholipid membranes are vital to the organization of the living cell. Based on fundamental principles of polarity, membranes create borders allowing defined spaces to be encapsulated. This compartmentalization is a prerequisite for the complex functional design of the eukaryotic cell, yielding localities that can differ in composition and operation. During macroautophagy, cytoplasmic components become enclosed by a growing double bilayered membrane, which upon closure creates a separate compartment, the autophagosome. The autophagosome is then primed for fusion with endosomal and lysosomal compartments, leading to degradation of the captured material. A large number of proteins have been found to be essential for autophagy, but little is known about the specific lipids that constitute the autophagic membranes and the membrane modeling events that are responsible for regulation of autophagosome shape and size. In this Commentary, we review the recent progress in our understanding of the membrane shaping and remodeling events that are required at different steps of the autophagy pathway.This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana SanchezWandelmer et al. (J. Cell Sci. 128,(185)(186)(187)(188)(189)(190)(191)(192) and 'WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome' by Tassula Proikas-Cezanne et al. (J. Cell Sci. 128,(207)(208)(209)(210)(211)(212)(213)(214)(215)(216)(217).

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Section: Phagophore Nucleationmentioning

confidence: 94%

Section: Phagophore Nucleationmentioning

confidence: 99%

Membrane dynamics in autophagosome biogenesis

Carlsson

Simonsen

2015

Journal of Cell Science

188

169

View full text Add to dashboard Cite

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“…Perhaps more importantly, the expression of vacuole membrane protein 1 (VMP1) is increased in AP and mediates "zymophagy," a selectively autophagic pathway to remove zymogen granules, and prevents pancreatic acinar cell death by interaction with Beclin1, an essential regulator of autophagy and apoptosis (71)(72)(73)(74). Mitochondrial injury and lipid abnormalities have been associated with pancreatitis (66).…”

Section: Autophagymentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

129

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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“…A great number of studies have previously demonstrated that the Beclin-1-Vps34-Vps15 multimeric complex can govern the nucleation of autophagy, as evidenced by the increased interaction between Beclin-1 and the Vps34-Vps15 complex in response to either starvation or rapamycin treatments (19,35,36). Given that Beclin-1 has been shown to interact physically with ErbB2 (37), we thus reasoned that ErbB2 could bind to Beclin-1 and modulate the autophagic flux to control the autophagic clearance of C99 and AICD.…”

Section: An Shrna Screen Identified Candidate Genes That Differentiallymentioning

confidence: 99%

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

Wang

Her

et al. 2017

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

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Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]-and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.ErbB2 | Alzheimer's disease | Aβ | C99 | autophagy A myloid plaques are the primary cause of neurodegeneration in the brains of patients with Alzheimer's disease (AD) (1). Amyloid plaques are composed of amyloid-β (Aβ) peptides that are produced by stepwise cleavages of amyloid precursor protein (APP) by β-and γ-secretase (2). Therapeutic approaches toward treatment of AD developed in the past decade have centered on the prevention of Aβ production (3). The majority of these studies focused on either the augmentation of α-secretase activity, which can reduce the production of Aβ, or the inhibition of β-/γ-secretase activities (4). Unfortunately, the nonselective inhibition of β-secretase and γ-secretase results in unavoidable side effects due to the interference of other physiological substrates of β-secretase and γ-secretase (5, 6).ErbB2 is a member of the epidermal growth factor receptor (EGFR)/ErbB family [which consists of four closely related receptor tyrosine kinases (ErbB1-4, also known as HER1-4)] and is tightly associated with neuritic plaques in AD (7). The correlation between EGFR/ErbB signaling and AD pathogenesis has been well documented in various studies (8-10). Ras GTPase activation mediates EGF-induced stimulation of γ-secretase to increase the nuclear function of the APP intracellular domain (AICD) (11). Consistent with the role of EGF signaling in AD, the intracellular mediators downstream of EGF signaling (which include Grb2, ShcA, and Abl) directly or indirectly interact with APP (12); these findings support the correlation between EGFR/ ErbB-dependent signaling and AD susceptibility.Autophagy controls the clearance of misfolded proteins and damaged organelles, and plays an essential role in maintaining neuronal functions (13,14). Previous studies have demonstrated that autophagy is instrumental to the clearance of proteins related to neurodegenerative diseases; these proteins include polyg...

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The VMP1-Beclin 1 interaction regulates autophagy induction

Cited by 148 publications

References 44 publications

Membrane dynamics in autophagosome biogenesis

Membrane dynamics in autophagosome biogenesis

Cell Death and DAMPs in Acute Pancreatitis

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

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