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Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes

Verma, Rati and Reichermeier, Kurt M. and Burroughs, A. Maxwell and Oania, Robert S. and Reitsma, Justin M. and Aravind, L. and Deshaies, Raymond J. (2018) Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes. Nature, 557 (7705). pp. 446-451. ISSN 0028-0836. PMCID PMC6226276. https://resolver.caltech.edu/CaltechAUTHORS:20180110-115638809

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Abstract

Ribosomal surveillance pathways scan for ribosomes that are transiently paused or terminally stalled owing to structural elements in mRNAs or nascent chain sequences. Some stalls in budding yeast are sensed by the GTPase Hbs1, which loads Dom34, a catalytically inactive member of the archaeo-eukaryotic release factor 1 superfamily. Hbs1–Dom34 and the ATPase Rli1 dissociate stalled ribosomes into 40S and 60S subunits. However, the 60S subunits retain the peptidyl-tRNA nascent chains, which recruit the ribosome quality control complex that consists of Rqc1–Rqc2–Ltn1–Cdc48–Ufd1–Npl4. Nascent chains ubiquitylated by the E3 ubiquitin ligase Ltn1 are extracted from the 60S subunit by the ATPase Cdc48–Ufd1–Npl4 and presented to the 26S proteasome for degradation. Failure to degrade the nascent chains leads to protein aggregation and proteotoxic stress in yeast and neurodegeneration in mice. Despite intensive investigations on the ribosome quality control pathway, it is not known how the tRNA is hydrolysed from the ubiquitylated nascent chain before its degradation. Here we show that the Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase. Similar to classical eukaryotic release factor 1, Vms1 activity is dependent on a conserved catalytic glutamine. Evolutionary analysis indicates that yeast Vms1 is the founding member of a clade of eukaryotic release factor 1 homologues that we designate the Vms1-like release factor 1 clade.


Item Type:Article
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https://dx.doi.org/10.1038/s41586-018-0022-5DOIArticle
https://www.nature.com/articles/s41586-018-0022-5PublisherArticle
https://rdcu.be/LmoEPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226276PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Alternate Title:Vms1/Ankzf1: A Novel Peptidyl-tRNA Hydrolase that Releases Nascent Chains from Stalled Ribosomes, Vms1/Ankzf1 is a peptidyl-tRNA hydrolase that releases nascent chains from stalled ribosomes
Additional Information:© 2018 Macmillan Publishers Limited. Received: 21 August 2017; Accepted: 8 February 2018; Published online 09 April 2018. We thank A. Buchberger, H. Rao, A. van Hoof, R. Voorhees and J. Warner for reagents; the Proteome Exploration Laboratory (PEL), Caltech, for help with the mass spectrometry analysis and the members of the Deshaies laboratory, M. Blanco, M. Guttman, B. Clemons, R. Voorhees and S. Shan for discussions. R.J.D. was an investigator of the HHMI and this work was funded in part by the HHMI. A.M.B. and L.A. are supported by the funds of the Intramural Research Program of the National Library of Medicine. Data reporting: All data shown are representative of at least two independent biological experiments. Reporting summary: Further information on experimental design is available in the Nature Research Reporting Summary linked to this paper. Data availability: Gel source images for Figs. 1, 3, 4 and Extended Data Figs. 1, 3 and 4 are available in Supplementary Fig. 1. Source Data for quantifications in Fig. 4 and Extended Data Fig. 4 are provided in the online version of the paper. All other data supporting the findings of this study are available from the corresponding authors upon reasonable request. Author Contributions: R.V., K.M.R. and R.J.D. designed experiments, J.M.R. performed mass spectrometry analyses, L.A. and A.M.B. did the computational analyses, K.M.R. performed the mutagenesis analyses, R.S.O. generated all the yeast strains and R.V. performed all the biochemical experiments. R.V. and R.J.D. supervised research, R.V., R.J.D. and L.A. wrote the paper and all authors participated in editing the manuscript. All figure schematics were generated by K.M.R. Competing interests: R.V., K.M.R., A.M.B., R.S.O., J.M.R. and L.A. declare no competing interests. R.J.D. is currently Senior Vice President of discovery research at Amgen and a Visiting Associate at the California Institute of Technology (Caltech).
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Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
National Library of MedicineUNSPECIFIED
Issue or Number:7705
PubMed Central ID:PMC6226276
Record Number:CaltechAUTHORS:20180110-115638809
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180110-115638809
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84231
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Apr 2018 15:01
Last Modified:03 Oct 2019 19:16

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