Open AccessIntercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression
Author(s) -
Yildirim Zehra,
Baboo Sabyasachi,
Hamid Syed M,
Dogan Asli E,
Tufanli Ozlem,
Robichaud Sabrina,
Emerton Christina,
Diedrich Jolene K,
Vatandaslar Hasan,
Nikolos Fotis,
Gu Yanghong,
Iwawaki Takao,
Tarling Elizabeth,
Ouimet Mireille,
Nelson David L,
Yates John R,
Walter Peter,
Erbay Ebru
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202115344
Subject(s) - endoplasmic reticulum , unfolded protein response , microbiology and biotechnology , kinase , phosphorylation , biology , protein kinase a
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.