# Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy

## TL;DR

This study shows that SIRT2 deacetylates HSC70, enhancing chaperone-mediated autophagy during starvation, which is crucial for maintaining cellular protein balance.

## Contribution

The novel finding is that SIRT2 regulates CMA through deacetylation of HSC70 at K557, linking lysine acetylation to proteostasis.

## Key findings

- SIRT2 deacetylates HSC70 at K557, increasing its substrate binding affinity during starvation.
- K557R mutation enhances CMA activity, while K557Q impairs it, confirming the role of acetylation.
- SIRT2 inhibition reduces CMA activity, which is restored by HSC70 K557R expression.

## Abstract

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.