Lysosomal Damage Promotes Autophagy-based Unconventional Secretion of the Parkinson’s Disease Protein PARK7
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Objective: PARK7/DJ-1 is a multifunctional protein and redox sensor essential for cellular survival and oxidative stress defense. Its unconventional secretion under oxidative stress is linked to the development of neurodegenerative diseases, cancer, and inflammation. This study investigates the mechanisms of PARK7 secretion in response to lysosomal membrane permeabilization (LMP) induced by L-Leucyl-L-Leucine methyl ester (LLOMe).
Methods: HeLa and MEF cells were treated with LLOMe, followed by washout with serum-free DMEM. PARK7 secretion was analyzed by assessing intracellular and extracellular protein levels.
Results: Upon LLOMe treatment, PARK7 translocates to damaged lysosomes, colocalizing with galectin-3 (Gal3), a marker of lysosomal injury. Following LLOMe washout, an increase in lysophagy flux was observed, enhancing the secretion of both PARK7 and Gal3. Knockdown of TANK-binding kinase 1 (TBK1), a critical lysophagy regulator, suppresses LLOMe-induced PARK7 secretion, confirming a lysophagy-dependent mechanism. Notably, while inhibition of autophagy initiation blocks PARK7 secretion, disruption of autophagosome-lysosome fusion does not affect its release. Additionally, the Sec22b-mediated SNARE complex, comprising STX3/4 and SNAP23/29, is essential for the fusion of secretory autophagosomes with the plasma membrane during PARK7 secretion.
Conclusion: These findings reveal a novel lysophagy-dependent mechanism of PARK7 secretion, where acute lysosomal damage facilitates the recruitment of PARK7 to damaged lysosomes, subsequent autophagosome encapsulation, and non-degradative release into the extracellular space through a dedicated SNARE complex.
Significance: These findings broaden the understanding of unconventional protein secretion under lysosomal stress and highlight potential therapeutic targets for diseases linked to lysosomal dysfunction, including neurodegeneration and inflammation.
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