Missense mutations change a single amino acid, but even these small changes can alter the folding, stability or localisation of the affected protein, which must be cleared by the protein quality control (PQC) network to avoid deleterious effects on cell function. A major pathway for clearance of cytosolic proteins is the ubiquitin proteasome system (UPS), in which client proteins are recognized by chaperones and tagged for degradation by the ubiquitin machinery. Different proteins are handled by a complex network of PQC factors. In this study (Baker et al., 2025), Thibault Mayor and colleagues identify factors that specifically affect the degradation of cytosolic missense mutants. Using 18 mutants found to be less stable than their wild-type counterparts, they show that these proteins are primarily degraded via the UPS. Focusing on the A80P missense mutant of thiopurine S-methyltransferase (TPMT), they compare proteins that interact with TPMT A80P versus wild-type TPMT, revealing enrichment of the HSP70 family co-chaperone DNAJA2, among other PQC-associated factors. DNAJA2 knockout decreases levels of A80P but not wild-type TPMT and preferentially destabilises two other missense mutant proteins, suggesting that DNAJA2 specifically ‘buffers’ the levels of some missense mutants against proteasomal degradation. This buffering, which has been previously observed for other chaperones, might assist the cell in the complex triage of certain misfolded proteins and protect against destabilising effects of missense mutations.
