Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression

EMBO Mol Med. 2022 Apr 7;14(4):e15344. doi: 10.15252/emmm.202115344. Epub 2022 Feb 22.


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: ER stress; atherosclerosis; cholesterol homeostasis; efferocytosis; translational regulation.

MeSH terms

  • Animals
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Atherosclerosis* / prevention & control
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • Fragile X Mental Retardation Protein* / metabolism
  • Membrane Proteins* / metabolism
  • Mice
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction


  • Fmr1 protein, mouse
  • Membrane Proteins
  • Fragile X Mental Retardation Protein
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases