Vms1p is a release factor for the ribosome-associated quality control complex

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.

Structural basis for bacterial ribosome quality control

“…Is there a dedicated termination factor that mediates release of the tagged nascent polypeptide chain in bacteria, analogous to Vms1/ANKZF1 in eukaryotes? (Kuroha et al, 2018;Su et al, 2019;Verma et al, 2018;Yip et al, 2019;Zurita Rendon et al, 2018). In summary, we demonstrate the involvement of YabO in RqcH-mediated bacterial RQC, and propose an alternative model for protein synthesis on the ribosome that utilizes binding and rebinding of two non-GTPase protein factors to execute a whole elongation cycle without the small ribosomal subunit or mRNA.…”

A comparative study of stress responses elicited by misfolded proteins targeted by bipartite or matrix-targeting signal sequences to yeast mitochondria

“…This role of Vms1 corroborates well with the observed growth phenotype aggravation of MM-PMD-vms1Δ cells during stress ( Figure 6C). been recently shown to harbour peptidyl-tRNA hydrolase/endonuclease activity in its VLRF1 domain 15,25,35 , we speculate that these activities of the protein is important for suspending the mitochondrial respiration as an adaptive response to matrix stress.…”

“…Interestingly, a substantial number of genes involved in cytosolic quality control like ssa1, ssa2, ssa4, hsp82, hsc82, ydj1, djp1, sis1, cct2 were found to be upregulated specifically in matrix stress ( Figure 3B). Importantly, component of Ribosome Quality Control (RQC), vms1, which is known to act as a peptidyl-tRNA endonuclease and protect mitochondria by antagonising the CAT-tailing activity of rqc2 15,25 was found to be specifically upregulated in matrix stress ( Figure 3B Figure S3A). Interestingly mdj1Δ did not aggravate the growth phenotype further while ecm10Δ (matrix hsp70) exhibited alleviation of growth phenotypes in both IMS and MM-PMD strains ( Figure S3A).…”

“…On the contrary, upon systematic genetic interactions with deletion strains of matrix stress specific upregulated genes, we found presence of Vms1 to be critical for mito-matrix-UPR. Vms1 is known as a key component of Mitochondria Associated Degradation (MAD) pathway [32][33][34] and an important player of Ribosome Quality Control of stalled ribosomes 14,15,25,35,36 . Deletion of vms1 in the matrix and IMS misfolding strains, revealed its explicit role in matrix misfolding stress ( Figure 6C).…”

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

“…Further studies revealed that Vms1 binds to ribosomes and the RQC complex, suggesting a role of RQC in mitochondrial quality control and a general function of Vms1 in RQC (Izawa et al, 2017). Indeed, Vms1 and its human homologue ANKZF1 have then been identified as peptidyl-tRNA hydrolase, required to remove the bound tRNA from the nascent chain, thereby facilitating release from the ribosome (Zurita Rendón et al, 2018;Verma et al, 2018).…”