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      • Department of Molecular Biology and Genetics
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      Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression

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      Author(s)
      Yıldırım, Zehra
      Baboo, S.
      Hamid, S.M.
      Doğan, Asli E.
      Tufanlı, Ö.
      Robichaud, S.
      Emerton, C.
      Diedrich, J.K.
      Vatandaşlar, H.
      Nikolos, F.
      Gu, Y.
      Iwawaki, T.
      Tarling, E.
      Ouimet, M.
      Nelson, D.L.
      Yates, J.R.
      Walter, P.
      Erbay, E.
      Date
      2022-02-22
      Source Title
      EMBO Molecular Medicine
      Electronic ISSN
      1757-4684
      Publisher
      EMBO Press
      Volume
      14
      Issue
      4
      Pages
      1 - 22
      Language
      English
      Type
      Article
      Item Usage Stats
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      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
      Permalink
      http://hdl.handle.net/11693/111792
      Published Version (Please cite this version)
      https://doi.org/10.15252/emmm.202115344
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