@article{1633c9b9097e422798dc8f8de6be978d,
title = "Cytosolic Protein Vms1 Links Ribosome Quality Control to Mitochondrial and Cellular Homeostasis",
abstract = "Eukaryotic cells have evolved extensive protein quality-control mechanisms to remove faulty translation products. Here, we show that yeast cells continually produce faulty mitochondrial polypeptides that stall on the ribosome during translation but are imported into the mitochondria. The cytosolic protein Vms1, together with the E3 ligase Ltn1, protects against the mitochondrial toxicity of these proteins and maintains cell viability under respiratory conditions. In the absence of these factors, stalled polypeptides aggregate after import and sequester critical mitochondrial chaperone and translation machinery. Aggregation depends on C-terminal alanyl/threonyl sequences (CAT-tails) that are attached to stalled polypeptides on 60S ribosomes by Rqc2. Vms1 binds to 60S ribosomes at the mitochondrial surface and antagonizes Rqc2, thereby facilitating import, impeding aggregation, and directing aberrant polypeptides to intra-mitochondrial quality control. Vms1 is a key component of a rescue pathway for ribosome-stalled mitochondrial polypeptides that are inaccessible to ubiquitylation due to coupling of translation and translocation. A quality-control pathway comprising the cytosolic protein Vms1 protects mitochondria from the toxic effects of ribosome-stalled polypeptides.",
keywords = "CAT-tails, Ltn1, Rqc2, Vms1, mitochondria, mitochondrial toxicity, protein aggregation, protein import, ribosome quality control, ribosome stalling",
author = "Toshiaki Izawa and Park, {Sae Hun} and Liang Zhao and Hartl, {F. Ulrich} and Walter Neupert",
note = "Funding Information: We thank T. Endo for Ssa1 and Hsp60 antibodies and the laboratory of S. Jentsch for Cdc48 antibodies, K. Okamoto for the mitochondrial mCherry construct, Y.-J. Choe for the Rqc2-FLAG constructs, and the MPIB Microchemistry Core Facility for mass spectrometry. We thank R. Koerner and A. Ries for help with proteomic analysis and Y.-J. Choe and M. Hayer-Hartl for discussion. W.N. acknowledges funding by the Max Planck Society as a senior fellow and by the Carl Friedrich von Siemens Foundation and thanks M. Kiebler for providing lab space and facilities. T.I. was supported by a postdoctoral fellowship of the Japan Society for the Promotion of Science, and W.N. is a senior fellow of the Max Planck Society. F.U.H. acknowledges funding by the European Commission under FP7 GA no. ERC-2012-SyG_318987 ? ToPAG, the Center for Integrated Protein Science Munich (CIPSM), and the Munich Cluster for Systems Neurology (SyNergy). Funding Information: We thank T. Endo for Ssa1 and Hsp60 antibodies and the laboratory of S. Jentsch for Cdc48 antibodies, K. Okamoto for the mitochondrial mCherry construct, Y.-J. Choe for the Rqc2-FLAG constructs, and the MPIB Microchemistry Core Facility for mass spectrometry. We thank R. Koerner and A. Ries for help with proteomic analysis and Y.-J. Choe and M. Hayer-Hartl for discussion. W.N. acknowledges funding by the Max Planck Society as a senior fellow and by the Carl Friedrich von Siemens Foundation and thanks M. Kiebler for providing lab space and facilities. T.I. was supported by a postdoctoral fellowship of the Japan Society for the Promotion of Science , and W.N. is a senior fellow of the Max Planck Society . F.U.H. acknowledges funding by the European Commission under FP7 GA no. ERC-2012-SyG_318987 – ToPAG , the Center for Integrated Protein Science Munich (CIPSM) , and the Munich Cluster for Systems Neurology (SyNergy) . Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
day = "2",
doi = "10.1016/j.cell.2017.10.002",
language = "English",
volume = "171",
pages = "890--903.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}