Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex

Abstract

SummaryAutophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead to the accumulation of misfolded proteins in neurons and might be involved in chronic neurodegenerative diseases. Here, we uncover an essential role for the syntaxin-5 SNARE complex in autophagy. Using genetic knockdown, we show that the syntaxin-5 SNARE complex regulates the later stages of autophagy after the initial formation of autophagosomes. This SNARE complex acts on autophagy by regulating ER-to-Golgi transport through the secretory pathway, which is essential for the activity of lysosomal proteases such as cathepsins. Depletion of syntaxin-5 complex components results in the accumulation of autophagosomes as a result of lysosomal dysfunction, leading to decreased degradation of autophagic substrates. Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system.

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

“…10,11 'Syntaxin 18 SNARE' complex was found to be implicated in membrane fusion of retrograde transport 10,56,57 while its members Sec22B and ZW10/RINT1 are also involved in the anterograde transport. 16,58 RINT1 was shown to be also involved in the more specific Rab6-dependent recycling pathway from the Golgi to the ER. 20 Disruption of the balance of the bi-directional ER/Golgi transport was shown to trigger Golgi fragmentation followed by ER stress.…”

“…65 Sec22B was shown to regulate clearance of autophagosomes indirectly by assuring the anterograde transport of lysosomal proteases from ER via Golgi to lysosomes. 58 In this context, Rint1 could be involved in the clearance of autophagosomes by a mechanism identical to Sec22B and its function in anterograde transport. An alternative mechanism that could explain the Rint1-deficient autophagic defects in neurons is the disruption of autophagosome transport.…”

Conditional Depletion of the Chlamydomonas Chloroplast ClpP Protease Activates Nuclear Genes Involved in Autophagy and Plastid Protein Quality Control

“…The induction of these genes is a typical hallmark of autophagy. Moreover, the set of highly upregulated mRNAs encode proteins involved in membrane biogenesis and vesicular trafficking, including two SNARE proteins (Vmpl2 and Vamp74) that catalyze the homotypic membrane fusion during the late stages of autophagosome formation both in mammalian cells and yeast (Nair et al, 2011;Renna et al, 2011;Stroupe, 2011).…”

Autophagy and proteins involved in vesicular trafficking

“…It is believed that STX5 regulates ER to Golgi transport allowing the maturation and transport of lysosomal proteases (i.e. cathepsins) [132].…”