Identification of a novel substrate of IRE1 in lipotoxic stress response

Abstract

Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is a ribonucleic acid (RNA)-binding protein (RBP) that controls translation of select messenger RNAs (mRNAs). I discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. I 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. The results presented in my thesis provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggest IRE1 inhibition could be developed as a promising new therapeutic strategy to counteract atherosclerosis.