@article{117b4ef102d44c1cb1b1ae76847b40b1,
title = "A role for the ribosome-associated complex in activation of the IRE1 branch of UPR",
abstract = "The ubiquitous ribosome-associated complex (RAC) is a chaperone that spans ribosomes, making contacts near both the polypeptide exit tunnel and the decoding center, a position prime for sensing and coordinating translation and folding. Loss of RAC is known to result in growth defects and sensitization to translational and osmotic stresses. However, the physiological substrates of RAC and the mechanism(s) by which RAC is involved in responding to specific stresses in higher eukaryotes remain obscure. The data presented here uncover an essential function of mammalian RAC in the unfolded protein response (UPR). Knockdown of RAC sensitizes mammalian cells to endoplasmic reticulum (ER) stress and selectively interferes with IRE1 branch activation. Higher-order oligomerization of the inositol-requiring enzyme 1α (IRE1α) kinase/endoribonuclease depends upon RAC. These results reveal a surveillance function for RAC in the UPR, as follows: modulating IRE1α clustering as required for endonuclease activation and splicing of the substrate Xbp1 mRNA.",
keywords = "IRE1 foci, UPR, Xbp1 mRNA, chaperone, ribosome stalling, ribosome-associated complex, translation",
author = "Wu, {I. Hui} and Yoon, {Jae Seok} and Qian Yang and Yi Liu and William Skach and Philip Thomas",
note = "Funding Information: Authors thank the following collaborators for kindly providing reagents and technical support: Dr. Elizabeth Craig{\textquoteright}s lab at the University of Wisconsin-Madison for the knockout RAC yeast strains; Dr. Peter Walter{\textquoteright}s lab at the UCSF for the T-REx293 IRE1-GFP cell line; Dr. Sabine Rospert{\textquoteright}s lab at the University of Freiburg, Germany, for anti-Mpp11 antibody; Dr. Ineke Braakman{\textquoteright}s Lab at the University Utrecht, the Netherlands, for one of the knockout Hsp70L1 cell lines (data not shown); Dr. Christopher Nicchitta at Duke University for critical technical advice regarding the differential detergent cell fractionation experiments; Dr. Benjamin Tu and his lab at UTSW for yeast technical support; Dr. Jen Liou{\textquoteright}s lab at UTSW for microscope technical support; and the microscope imaging core at the physiology department at UTSW. This research was supported by the cancer biology program and the mechanisms of disease and translational science (MoDTS) graduate track at UTSW and HHMI Med into grad initiative to I.-H.W., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (grant R37DK49835 ) and Ruth S. Harrell Professorship to P.T., and National Institutes of Health ( R35GM118118 ) and the Welch Foundation ( I-1560 ) to Y.L. Funding Information: Authors thank the following collaborators for kindly providing reagents and technical support: Dr. Elizabeth Craig's lab at the University of Wisconsin-Madison for the knockout RAC yeast strains; Dr. Peter Walter's lab at the UCSF for the T-REx293 IRE1-GFP cell line; Dr. Sabine Rospert's lab at the University of Freiburg, Germany, for anti-Mpp11 antibody; Dr. Ineke Braakman's Lab at the University Utrecht, the Netherlands, for one of the knockout Hsp70L1 cell lines (data not shown); Dr. Christopher Nicchitta at Duke University for critical technical advice regarding the differential detergent cell fractionation experiments; Dr. Benjamin Tu and his lab at UTSW for yeast technical support; Dr. Jen Liou's lab at UTSW for microscope technical support; and the microscope imaging core at the physiology department at UTSW. This research was supported by the cancer biology program and the mechanisms of disease and translational science (MoDTS) graduate track at UTSW and HHMI Med into grad initiative to I.-H.W. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (grant R37DK49835) and Ruth S. Harrell Professorship to P.T. and National Institutes of Health (R35GM118118) and the Welch Foundation (I-1560) to Y.L. I.-H.W. conceived, designed, and conduced the majority of the experiments; analyzed data; designed figures; and wrote the manuscript. J.S.Y. and W.S. performed the ribosome-profiling experiments and analysis and edited the manuscript. Q.Y. and Y.L. assisted with in vitro translation lysate production, performed the luciferase assay, and edited the manuscript. P.T. provided support and guidance and wrote the manuscript. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jun,
day = "8",
doi = "10.1016/j.celrep.2021.109217",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}