@article{f2dea1e7ea024de98a89d5ffd650a932,
title = "Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression",
abstract = "Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.",
keywords = "atherosclerosis, cholesterol homeostasis, efferocytosis, ER stress, translational regulation",
author = "Zehra Yildirim and Sabyasachi Baboo and Hamid, {Syed M.} and Dogan, {Asli E.} and Ozlem Tufanli and Sabrina Robichaud and Christina Emerton and Diedrich, {Jolene K.} and Hasan Vatandaslar and Fotis Nikolos and Yanghong Gu and Takao Iwawaki and Elizabeth Tarling and Mireille Ouimet and Nelson, {David L.} and Yates, {John R.} and Peter Walter and Ebru Erbay",
note = "Funding Information: We express our appreciation to Jennifer C. Darnell (The Rockefeller University, New York) for providing and guiding with Fmr1 plasmid and to Roberta Gottlieb and Juliana Germano (Cedars‐Sinai Medical Center) for their guidance with polysome profiling. National Institutes of Health grant R01HL152156 (EE), Cedars‐Sinai Medical Center Internal Support (EE), National Institutes of Health grant R01GM32384 (PW), Investigator of the Howar Hughes Medical Institute (PW), National Institutes of Health grant P41GM103533 (JRY), Vanier Canada Graduate Scholarship (SR), Canadian Institutes for Health Research PJT‐391187 (MO). This study was funded by the following: Funding Information: We express our appreciation to Jennifer C. Darnell (The Rockefeller University, New York) for providing and guiding with Fmr1 plasmid and to Roberta Gottlieb and Juliana Germano (Cedars-Sinai Medical Center) for their guidance with polysome profiling. This study was funded by the following: National Institutes of Health grant R01HL152156 (EE), Cedars-Sinai Medical Center Internal Support (EE), National Institutes of Health grant R01GM32384 (PW), Investigator of the Howar Hughes Medical Institute (PW), National Institutes of Health grant P41GM103533 (JRY), Vanier Canada Graduate Scholarship (SR), Canadian Institutes for Health Research PJT-391187 (MO). Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2022",
month = apr,
day = "7",
doi = "10.15252/emmm.202115344",
language = "English (US)",
volume = "14",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley",
number = "4",
}