Acetylation promotes mutant (MUT) TP53-HSPA8 and HSPA8-BAG3 interactions, facilitating MUT TP53 lysosomal degradation preferentially via CASA.

Targeting mutant (MUT) TP53 is crucial in anticancer therapy, given the oncogenic properties that these proteins often acquire. Therefore, it is of paramount importance to unravel strategies and mechanisms through which this goal can be achieved. Valproic acid (VPA) downregulates the expression of MUT TP53 in several tumor cells, although the mechanisms involved remain to be explored. Here, we demonstrate for the first time that acetylation induced by VPA promotes the lysosomal degradation of MUT TP53 and that it occurs preferentially through chaperone-assisted selective autophagy (CASA). Indeed, acetylation of MUT TP53 increases its interaction with STUB1 (STIP1 homology and U-box containing protein 1), HSPB8 (heat shock protein family B (small) member 8) and HSPA8 (heat shock protein family A (Hsp70) member 8) and the latter, itself acetylated by VPA, binds to BAG3 (BAG cochaperone 3), facilitating the recruitment of MUT TP53 into the CASA pathway. These findings elucidate the mechanisms through which acetylation leads to the selective lysosomal clearance of MUT TP53, highlighting a potential therapeutic vulnerability of aggressive tumors expressing this oncoprotein.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; BAF: bafilomycin A1; CMA: chaperone-mediated autophagy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; SQSTM1: sequestosome 1; TP53: tumor protein p53.