Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia

Naydenov, Nayden G.; Harris, Gianni; Morales, Víctor; Ivanov, Andrei I.

doi:10.4161/cc.22885

Cited by 40 publications

(42 citation statements)

References 76 publications

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“…Depletion of the soluble N -ethylmaleimide-sensitive factor attachment protein α (αSNAP) by siRNA in cultured epithelial cells has been shown to stimulate autophagy, decrease mTOR signaling and lead to Golgi fragmentation [154]. Loss of αSNAP also results in the down-regulation of GBF1, BIG1 and BIG2 proteins.…”

Section: Effects Of Cell Physiology On Gef Functionmentioning

confidence: 99%

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Wright

Kahn

Sztul

2014

Cell. Mol. Life Sci.

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Eukaryotic cells require selective sorting and transport of cargo between intracellular compartments. This is accomplished at least in part by vesicles that bud from a donor compartment, sequestering a subset of resident protein “cargos” destined for transport to an acceptor compartment. A key step in vesicle formation and targeting is the recruitment of specific proteins that form a coat on the outside of the vesicle in a process requiring the activation of regulatory GTPases of the ARF family. Like all such GTPases, ARFs cycle between inactive, GDP-bound, and membrane-associated active, GTP-bound, conformations. And like most regulatory GTPases the activating step is slow and thought to be rate limiting in cells, requiring the use of ARF guanine nucleotide exchange factor (GEFs). ARF GEFs are characterized by the presence of a conserved, catalytic Sec7 domain, though they also contain motifs or additional domains that confer specificity to localization and regulation of activity. These domains have been used to define and classify five different sub-families of ARF GEFs. One of these, the BIG/GBF1 family, includes three proteins that are each key regulators of the secretory pathway. GEF activity initiates the coating of nascent vesicles via the localized generation of activated ARFs and thus these GEFs are the upstream regulators that define the site and timing of vesicle production. Paradoxically, while we have detailed molecular knowledge of how GEFs activate ARFs, we know very little about how GEFs are recruited and/or activated at the right time and place to initiate transport. This review summarizes the current knowledge of GEF regulation and explores the still uncertain mechanisms that position GEFs at “budding ready” membrane sites to generate highly localized activated ARFs.

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Section: Effects Of Cell Physiology On Gef Functionmentioning

confidence: 99%

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Wright

Kahn

Sztul

2014

Cell. Mol. Life Sci.

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“…Interestingly, the observed cellular defects in the intestinal mucosa of hyh mutant mice were much less evident as compared to the severe abnormalities caused by the αSNAP knockdown in model human intestinal epithelial cell monolayers. Indeed, in cultured epithelial cells, loss of αSNAP resulted in dramatic disorganization of the epithelial architecture manifested by the loss of cell-cell and cell-matrix adhesion and significant cell death [13–16]. None of these effects was detected in the small or large intestine of hyh mutant mice where epithelial cells retained robust apical junctions and showed no signs of excessive cell detachment or death (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple NSF-independent functions of αSNAP have been reported in cultured intestinal epithelial cells. They include regulation of epithelial junctions, cell migration, apoptosis, and autophagy [13–16]. However, no previous studies have addressed the roles of αSNAP in the regulation of intestinal epithelial homeostasis in vivo.…”

Section: Introductionmentioning

confidence: 99%

A vesicle trafficking protein αSNAP regulates Paneth cell differentiation in vivo

Lechuga

Naydenov

Feygin

et al. 2017

Biochemical and Biophysical Research Communications

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A soluble N-ethylmaleimide-sensitive factor-attachment protein alpha (αSNAP) is a multifunctional scaffolding protein that regulates intracellular vesicle trafficking and signaling. In cultured intestinal epithelial cells, αSNAP has been shown to be essential for cell survival, motility, and adhesion; however, its physiologic functions in the intestinal mucosa remain unknown. In the present study, we used a mouse with a spontaneous hydrocephalus with hop gait (hyh) mutation of αSNAP to examine the roles of this trafficking protein in regulating intestinal epithelial homeostasis in vivo. Homozygous hyh mice demonstrated decreased expression of αSNAP protein in the intestinal epithelium, but did not display gross abnormalities of epithelial architecture in the colon and ileum. Such αSNAP depletion attenuated differentiation of small intestinal epithelial enteroids ex vivo. Furthermore, αSNAP-deficient mutant animals displayed reduced formation of lysozyme granules in small intestinal crypts and decreased expression of lysozyme and defensins in the intestinal mucosa, which is indicative of defects in Paneth cell differentiation. By contrast, development of Goblet cells, enteroendocrine cells, and assembly of enterocyte apical junctions was not altered in hyh mutant mice. Our data revealed a novel role of αSNAP in the intestinal Paneth cell differentiation in vivo.

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“…These intriguing observations add to a growing body of evidence indicating that important cellular functions of ␣SNAP can be executed via NSF-independent mechanisms. Examples of such NSF-independent functions include regulation of apical plasma membrane trafficking (79) and integrity of apical junctions in polarized epithelial cells (34), as well as control of cell survival (35) and autophagy (36). A recent study has described a novel role of ␣SNAP in regulating mitochondrial biogenesis via direct interaction and dephosphorylation of AMP-activated protein kinase (37).…”

Section: Discussionmentioning

confidence: 99%

“…Brefeldin A and Golgicide A are known to have one common molecular target, Golgi brefeldin factor 1 (GBF1), which serves as guanine nucleotide exchange factors for Golgi-resident ARF small GTPases (49 -51). Previously, we demonstrated that loss of ␣SNAP decreased GBF1 expression in SK-CO15 cells and that GBF1 knockdown mimicked major effects of ␣SNAP depletion on epithelial junctions and the autophagic flux (34,36). Therefore, we sought to investigate if loss of GBF1 can recapitulate disruption of ECM adhesion observed in ␣SNAP knockdown.…”

Section: Disruption Of the Golgi Recapitulates The Effects Of ␣Snap Kmentioning

confidence: 99%

N-Ethylmaleimide-sensitive Factor Attachment Protein α (αSNAP) Regulates Matrix Adhesion and Integrin Processing in Human Epithelial Cells

Naydenov

Feygin

Wang

et al. 2014

Journal of Biological Chemistry

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Background: Vesicle trafficking plays important roles in regulating cell adhesion and motility. Results: Depletion of the membrane fusion protein, N-ethylmaleimide-sensitive factor attachment protein ␣ (␣SNAP), induced cell detachment, whereas overexpression of this vesicle regulator increased cell-matrix adhesion. Conclusion: ␣SNAP promotes cell-matrix adhesion by controlling integrin trafficking and assembly of focal adhesions. Significance: The ␣SNAP level may serve as a molecular rheostat controlling matrix adhesion and cell motility under normal conditions and in diseases.

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Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia

Cited by 40 publications

References 76 publications

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

A vesicle trafficking protein αSNAP regulates Paneth cell differentiation in vivo

N-Ethylmaleimide-sensitive Factor Attachment Protein α (αSNAP) Regulates Matrix Adhesion and Integrin Processing in Human Epithelial Cells

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