REGULATION OF CHAPERONE-MEDIATED AUTOPHAGY AND TRANSLATIONAL FIDELITY VIA POST-TRANSLATIONAL MODIFICATIONS
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Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway essential for proteostasis, regulated by HSC70 (HSPA8) recognition of substrates containing KFERQ-like motifs. My work shows that the NAD⁺-dependent deacetylase SIRT2 promotes CMA activation by deacetylating HSC70 at lysine 557 (K557), enhancing its substrate binding during nutrient deprivation. In parallel, my work also investigate diphthamide (DPH), a posttranslational modification in eEF2, and its impact on DNA damage and replication stress. Using computational profiling and quantitative proteomics, we identify RRM1 as a key protein whose translation is modulated by diphthamide through −1 frameshifting. This dysregulation of RRM1 translation in DPH-deficient cells contributes to DNA replication stress and provides a potential link between diphthamide deficiency, cancer, and developmental defects. Together, these studies highlight the critical roles of SIRT2-mediated HSC70 deacetylation and diphthamide in cellular stress responses and proteostasis, with implications for neurodegenerative diseases and cancer.