Ubiquitylation-independent cotranslational degradation of dihydrofolate reductase and ubiquitin

Nascent proteins are degraded during or immediately after synthesis, a process called cotranslational protein degradation (CTPD). Although CTPD was observed decades ago, it has never been fully explored mechanistically and functionally. We show here that dihydrofolate reductase (DHFR) and ubiquitin (Ub), two stable proteins widely used in protein degradation studies, are actually subject to CTPD. Unlike canonical posttranslational protein degradation, CTPD of DHFR and Ub does not require prior ubiquitylation. Our data also suggest that protein expression level and N-terminal folding pattern may be two critical determinants for CTPD. Thus, this study reveals that CTPD plays a role in regulating the homeostasis of long-lived proteins and provides insights into the mechanism of CTPD. •Dihydrofolate reductase (DHFR) and ubiquitin (Ub) are subject to cotranslational protein degradation (CTPD).•CTPD may play a role in regulating the homeostasis of long-lived proteins.•Unlike canonical posttranslational protein degradation, CTPD of DHFR and Ub does not require prior ubiquitylation.•CTPD efficiency may be determined by protein expression levels and N-terminal folding patterns.