Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy.

Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation essential for cellular proteostasis. CMA is activated during cellular stress, such as starvation, and involves the chaperone protein HSC70 (HSPA8) recognizing substrates containing KFERQ-like motifs. However, the regulatory mechanisms governing CMA activation remain poorly understood. Here, we demonstrate that the NAD+ -dependent deacetylase SIRT2 promotes CMA activation by deacetylating HSC70 at lysine 557 (K557). Our findings reveal that SIRT2 activity is upregulated during starvation, enhancing its interaction with HSC70 and facilitating the deacetylation of K557. Deacetylation of HSC70 at K557 increases its binding affinity to CMA substrates, thereby promoting their lysosomal degradation. Mutation of K557 to a deacetylation-mimetic arginine (K557R) enhances CMA activity under both nutrient-rich and starvation conditions, while the acetylation-mimetic glutamine mutant (K557Q) impairs substrate binding and CMA activation. Furthermore, the inhibition or knockdown of SIRT2 reduces CMA activity, which is rescued by HSC70 K557R expression. These findings identify SIRT2-mediated deacetylation of HSC70 as a regulatory mechanism for CMA activation during nutrient deprivation and highlight the role of protein lysine acetylation in proteostasis. This study provides insights into the interplay between SIRT2, HSC70, and CMA, with potential implications for diseases linked to proteostasis dysregulation, including neurodegenerative disorders and cancer.