Journal
CELL CYCLE
Volume 11, Issue 24, Pages 4613-4625Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.22885
Keywords
Beclin1; NSF; mTOR; Bif-1; vesicle trafficking; Golgi disruption
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Funding
- National Institute of Health [RO1 DK083968, R01 DK084953]
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Autophagy is a catabolic process that sequesters intracellular proteins and organelles within membrane vesicles called autophagosomes with their subsequent delivery to lyzosomes for degradation. This process involves multiple fusions of autophagosomal membranes with different vesicular compartments; however, the role of vesicle fusion in autophagosomal biogenesis remains poorly understood. This study addresses the role of a key vesicle fusion regulator, soluble N-ethylmaleimide-sensitive factor attachment protein a (alpha SNAP), in autophagy. Small interfering RNA-mediated downregulation of aSNAP expression in cultured epithelial cells stimulated the autophagic flux, which was manifested by increased conjugation of microtubule-associated protein light chain 3 (LC3-II) and accumulation of LC3-positive autophagosomes. This enhanced autophagy developed via a non-canonical mechanism that did not require beclin1-p150-dependent nucleation, but involved Atg5 and Atg7-mediated elongation of autophagosomal membranes. Induction of autophagy in aSNAP-depleted cells was accompanied by decreased mTOR signaling but appeared to be independent of aSNAP-binding partners, N-ethylmaleimide-sensitive factor and BNIP1. Loss of aSNAP caused fragmentation of the Golgi and downregulation of the Golgi-specific GTP exchange factors, GBF1, BIG1 and BIG2. Pharmacological disruption of the Golgi and genetic inhibition of GBF1 recreated the effects of aSNAP depletion on the autophagic flux. Our study revealed a novel role for aSNAP as a negative regulator of autophagy that acts by enhancing mTOR signaling and regulating the integrity of the Golgi complex.
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