Turnover of missense mutant cytosolic proteins proceeds in the absence of major quality control E3 ligases.

Protein quality control (QC) safeguards cellular proteostasis by directing misfolded proteins for degradation via the ubiquitin-proteasome system. QC is compartmentalized within cells, and the key proteins involved in the turnover of cytosolic proteins with mutations in mammalian cells are not well defined. Using a fluorescent reporter assay that provides a readout for protein stability, we examined the contributions of known QC E3 ligases (STUB1, UBE2O, UBR4, UBR5, and HUWE1) on the turnover of disease-associated missense variants. Loss of individual ligases did not consistently stabilize substrates, indicating that none of these E3s appear to broadly recognize missense mutant proteins.