Vms1 is a release factor for the Ribosome Quality control Complex Olga Zurita Rendón1,2*, Eric Fredrickson2*, Conor Howard3,5,6*, Christopher Hill2, Adam Frost2,3,6, Jared Rutter1,2 1HHMI, 2Department of Biochemistry, University of Utah School of Medicine, UT, USA 3Department of Biochemistry and Biophysics, University of California, CA, USA 5Department of Microbiology and Immunology, University of California, CA, USA 6California Institute for Quantitative Biomedical Research, CA USA Defects that impair the proper read-out of an mRNA during translation can cause ribosomes to stall. To prevent the accumulation of potentially deleterious nascent chains (NC) and to maintain ribosome homeostasis, eukaryotic cells employ surveillance and clearance mechanisms, including the Ribosome Quality Control (RQC) complex. In yeast, the RQC is comprised of the E3 ubiquitin ligase Ltn1, the ATPase Cdc48 and the poorly characterized proteins Rqc1 and Rqc2. The RQC assembles on 60S ribosomal subunits containing incomplete polypeptides linked to a tRNA. Rqc2 non-canonically synthesizes the C-term addition of poly-Ala and Thr extensions (CAT-tails) to the NC. The primary function of CAT-tailing is to expose from the exit tunnel Lys residues in the NC allowing ubiquitination by Ltn1, which stimulates Cdc48-dependent degradation. If the proteasome system is overwhelmed, CAT-tails mediate the formation of aggregates. A primary unanswered question concerns the identity of the hydrolase that liberates ubiquitinated and CAT-tailed NC from tRNA for degradation. The majority of the nuclear-encoded mitochondrial genome is imported into mitochondria in a co-translational fashion. Therefore, understanding the mechanisms that secure mito-translation fidelity is key for the maintenance of mitochondrial health. In this work, we show that the mitochondrial stress-responsive protein, Vms1 genetically interacts with all RQC components and the mRNA degradation protein, Ski7. Vms1 associates with Rqc2 and the 60S and prevents the accumulation/aggregation of cytosolic and mitochondrial reporters engineered to stall translation. Finally, our high-resolution structural data reveals that Vms1 harbors an eRF1 release factor-like domain that is required for both the genetic functions in living cells and release factor enzymatic activity in vitro. Our data demonstrate that Vms1 (ANKZF1 in humans) plays an essential role in the RQC pathway by catalyzing the hydrolysis of stalled peptidyl-tRNA species.
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