Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis

Journal home page for Journal of Biological ChemistryAuthor links open overlay panel, , Abstract

Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown of a modulator for autophagosome formation, ATG5, BECN1 or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein, which is an aggregate-prone protein responsible for neuronal loss in Parkinson’s disease. The blockade of autophagic secretion by knockdown of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these knockdowns induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 knockdown caused accumulation of Triton X-100-insoluble α-synuclein against induction of lysophagy. GBA knockdown showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, knockdown blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4 or RAB8A knockdown further accelerated accumulation of Triton X-100-insoluble α-synuclein caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4 or RAB8A knockdown blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these knockdowns impair α-synuclein proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.

Key words

autophagy

lysosome

Parkinson disease

proteostasis

protein secretion

synuclein

® 2025 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.

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