Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression

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.

Exploring the IRE1 interactome: From canonical signaling functions to unexpected roles

“…Liu and colleagues also showed that IRE1 interacts and promotes AMP-activated protein kinase phosphorylation exerting prosurvival signaling, nevertheless the direct/indirect modification remains unclear ( 119 ). The fragile X mental retardation protein (FMRP) was also identified as a new IRE1 kinase substrate, possibly regulating cholesterol transport and efferocytosis ( 150 ). In addition, pumilio, a RNA-binding protein in drosophila , was shown to be phosphorylated by IRE1, allowing its binding to XBP1 mRNA and protecting it against IRE1 RIDD activity ( 151 ).…”

RNA modification-mediated translational control in immune cells

“…Drosophila FMR1 preferentially binds mRNAs containing m 6 A-marked ‘AGACU’ motif, which is mainly dependent on the hydrophobic network within FMR1 KH2 domain and contributes to maternal RNA degradation [ 60 ]. FMRP, positively regulated by IRE1, was also found to act as a translation repressor via polyribosome profiling and promote atherosclerosis by affecting macrophage cholesterol metabolism [ 61 ]. The discovery of novel m 6 A-recognizable RBPs will greatly facilitate our understanding of the role of RNA modifications in regulating immune cell function Figure 1C ).…”

Crosstalk between endoplasmic reticulum stress and non‐coding RNAs in cardiovascular diseases

“…IRE1 inhibition leads to a remarkable reduction of plasma IL‐1β and IL‐18 levels in apolipoprotein E‐deficient mice (Tufanli et al, 2017). In addition, pharmacological suppression of IRE1 activity increases cholesterol efflux and apoptotic cell clearance, thereby reducing atherosclerosis in mice (Yildirim et al, 2022).…”