Abstract
Eukaryotic cells employ the ribosome-associated quality control complex (RQC) to maintain homeostasis despite defects that cause ribosomes to stall. The RQC comprises the E3 ubiquitin ligase Ltn1p, the ATPase Cdc48p, Rqc1p, and Rqc2p. Upon ribosome stalling and splitting, the RQC assembles on the 60S species containing unreleased peptidyl-tRNA (60S:peptidyl–tRNA). Ltn1p and Rqc1p facilitate ubiquitination of the incomplete nascent chain, marking it for degradation. Rqc2p stabilizes Ltn1p on the 60S and recruits charged tRNAs to the 60S to catalyze elongation of the nascent protein with carboxy-terminal alanine and threonine extensions (CAT tails). By mobilizing the nascent chain, CAT tailing can expose lysine residues that are hidden in the exit tunnel, thereby supporting efficient ubiquitination. If the ubiquitin–proteasome system is overwhelmed or unavailable, CAT-tailed nascent chains can aggregate in the cytosol or within organelles like mitochondria. Here we identify Vms1p as a tRNA hydrolase that releases stalled polypeptides engaged by the RQC.
Highlights
Eukaryotic cells employ the ribosome-associated quality control complex (RQC) to maintain homeostasis despite defects that cause ribosomes to stall
We show that Vms1p interacts genetically and physically with the RQC components, harbors an eukaryotic peptide chain release factor subunit 1 (eRF1) release factor-like domain, and is required for peptidyltRNA hydrolysis and clearance of RQC-engaged nascent chains
Deletion of the no-go decay[7,27] components DOM34 or SKI7 had no effect. These data suggest that CHX causes accumulation of an RQC product that becomes toxic in the absence of Vms1p
Summary
Eukaryotic cells employ the ribosome-associated quality control complex (RQC) to maintain homeostasis despite defects that cause ribosomes to stall. Rqc2p recruits charged tRNAs to the 60S subunit to catalyze elongation of the nascent protein with Carboxy-terminal Alanine and Threonine extensions (CAT tails) via a 40S-independent mechanism that is distinct from canonical translation[11,17] This non-templated elongation of the nascent chain can mobilize potential ubiquitination sites, including lysine residues that are hidden in the ribosome exit tunnel, enhancing the efficiency of ubiquitination and the capacity of the RQC to protect cells from stochastic translation failures[17,18]. We show that Vms1p interacts genetically and physically with the RQC components, harbors an eRF1 release factor-like domain, and is required for peptidyltRNA hydrolysis and clearance of RQC-engaged nascent chains This role of Vms1p in promoting proteostasis and ribosome recycling by resolving 60S:peptidyl-tRNA species expands upon the previously characterized function of Vms1p as a Cdc48/p97 binding protein and raises interesting new questions regarding the potential intersection of protein and organelle homeostasis
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