@article{1daa35b76184491c85cd50c599447cc8,
title = "Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth",
abstract = "The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P-3) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P-3 levels in macrophages. The modulation of cellular PI(3,4,5)P-3/PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.",
keywords = "ER stress, microRNA, mTOR signaling, hyperlipidemia, macrophage, ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, ER STRESS, HEPATIC STEATOSIS, MICRORNA TARGETS, PATHWAY, CELL, METABOLISM, MTOR, ATHEROSCLEROSIS",
author = "Hamid, {Syed Muhammad} and Mevlut Citir and Terzi, {Erdem Murat} and Ismail Cimen and Zehra Yildirim and Dogan, {Asli Ekin} and Begum Kocaturk and Onat, {Umut Inci} and Moshe Arditi and Christian Weber and Alexis Traynor-Kaplan and Carsten Schultz and Ebru Erbay",
note = "Funding Information: We are grateful to Dr. Gokhan S. Hotamisligil (Harvard School of Public Health) for providing the mouse embryonic fibroblasts, to Dr. Peter Walter (University of California, San Francisco) for the IRE1 plasmids and for the IRE1flox/flox mice Dr. Takao Iwawaki (Kanazawa Medical University). We express our appreciation to all members of Ebru Erbay and Roberta Gottlieb laboratories for insightful discussions on the manuscript. This work was supported by the European Research Council StG 336643 to E.E. European Research Council AdG 692511 and Deutsche Forschungsgemeinschaft (SFB 1123 and TRR 267‐A02) to C.W. C.S. and M.C. were partially supported by the Deutsche Forschungsgemeinschaft (DFG Transregio 83 and 186). C.W. is a Van de Laar professor of atherosclerosis. B.K. was partially supported by Fulbright scholarship (FY‐2017‐TR‐PD‐01). Funding Information: We are grateful to Dr. Gokhan S. Hotamisligil (Harvard School of Public Health) for providing the mouse embryonic fibroblasts, to Dr. Peter Walter (University of California, San Francisco) for the IRE1 plasmids and for the IRE1flox/flox mice Dr. Takao Iwawaki (Kanazawa Medical University). We express our appreciation to all members of Ebru Erbay and Roberta Gottlieb laboratories for insightful discussions on the manuscript. This work was supported by the European Research Council StG 336643 to E.E. European Research Council AdG 692511 and Deutsche Forschungsgemeinschaft (SFB 1123 and TRR 267-A02) to C.W. C.S. and M.C. were partially supported by the Deutsche Forschungsgemeinschaft (DFG Transregio 83 and 186). C.W. is a Van de Laar professor of atherosclerosis. B.K. was partially supported by Fulbright scholarship (FY-2017-TR-PD-01). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = dec,
day = "3",
doi = "10.15252/embr.202051462",
language = "English",
volume = "21",
journal = "Embo Reports",
issn = "1469-221X",
publisher = "Wiley",
number = "12",
}