Walter Lab

  • Walter Lab
  • Research
    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
  • Lab Members
    • Current
    • Alumni
  • Contact Us
  • Social
  • Publications
  • News & Notes

Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression

Yildirim Z, Baboo S, Hamid SM, Dogan AE, Tufanli O, Robichaud S, Emerton C, Diedrich JK, Vatandaslar H, Nikolos F, Gu Y, Iwawaki T, Tarling E, Ouimet M, Nelson DL, Yates JR 3rd, Walter P, Erbay E. Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO Mol Med 14(4):e15344, 2022
(PMCID : PMC8988208) (PMID : 35191199) (PDF)

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.

DOI: 10.15252/emmm.202115344


Deprecated: genesis_footer_creds_text is deprecated since version 3.1.0! Use genesis_pre_get_option_footer_text instead. This filter is no longer supported. You can now modify your footer text using the Theme Settings. in /nas/content/live/wlabdemo/wp-includes/functions.php on line 5698

Copyright © 2022  Walter Lab | University of California, San Francisco | Howard Hughes Medical Institute