BAG6 and RNF126 are broadly involved in protein quality control
We combine genome-wide CRISPR knockout screening with variant abundance by massively parallel sequencing (VAMP-seq) to identify components regulating PQC of Parkin missense variants. We find that HSP90 and STIP1 stabilize Parkin, while the BAG6 chaperone complex and E3 ubiquitin ligase RNF126 are critical for PQC degradation of essentially all low abundance and non-native Parkin variants, including several variants linked to autosomal recessive juvenile Parkinsonism. Pathogenic missense variants in phenylalanine hydroxylase (PAH) and the tumor suppressor FLCN are also BAG6 and RNF126 targets. We propose that BAG6 and RNF126 are broadly involved in PQC and may represent targets for the development of therapeutics for protein misfolding diseases.