Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth

Abstract

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X boxbinding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P 3) 5phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P 3 levels in macrophages. The modulation of cellular PI(3,4,5)P 3 /PIP 2 ratio and anabolic mTOR signaling by the IRE1induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis

“…IRE1 conditional knock out (Ern1 fl/fl ) mice were a kind gift from Dr. Takao Iwawaki (Kanazawa Medical University, Japan) and characterized previously (40). Ern1 fl/fl mice were crossed from with LysM cre mice to obtain LysM Cre+ Ern1 Δ/Δ mice, which had a myeloid-specific IRE1 gene deletion, as previously described (59). As LCWE-injection induces a stronger vasculitis in male mice than female mice, only male mice were used in this study (9,11).…”

Regulation of lipid metabolism by the unfolded protein response

“…For example, miR‐34 and miR‐200 , two miRNAs that are known to down‐regulate PPARα and SIRT1 expression in mouse liver, 83 have also been identified as RIDD targets 56,84 . Furthermore, a recent paper demonstrating unconventional IRE1‐dependent maturation of miR‐2137 in macrophages links RIDD with phosphatidylinositide‐derived signalling lipid metabolites and downstream signalling by mTOR, since phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3) 5‐ phosphatase‐2 (INPPL1) is a direct target of miR‐2137 85 …”

IRE1‐mediated miRNA maturation in macrophage phosphoinositide signaling

“…Together, these findings highlight the complexity of miRNA regulation by IRE1, which can either increase or decrease miRNA expression. In this issue, Hamid and colleagues add a novel layer of IRE1‐dependent regulation of the miRNA circuits showing that IRE1 can directly control the maturation of miR‐2137 in a Dicer‐independent manner (Hamid et al , 2020). The authors further provide evidence for a physiological role of this novel mechanism in the regulation of phosphoinositide levels in macrophages (Fig 1).…”

“…The most evolutionarily conserved one, the inositol-requiring enzyme 1 alpha (IRE1), transduces most of the signals through an endoribonuclease (RNase) activity toward RNAs including mRNAs and microRNAs (miRNAs). By exploring phosphoinositide signaling in human macrophages, Hamid and colleagues discovered a novel function of IRE1 RNase that through the cleavage of pre-miR-2317 generates a mature miR-2317 independently of the canonical Dicer endonuclease to yield specific biological outcomes (Hamid et al, 2020).…”

“…integrating (i) XBP1s activity as a source of pri-miRNA expression; (ii) RIDD pathway as a repressor of miRNA functions (miRIDD); and (iii) the novel Dicer-independent IRE1 RNase function described by Hamid et al (2020) as part of the maturation process of pre-miRNAs. Of note, IRE1 itself and XBP1s could also be targets of miRNAs, adding another layer of complexity (McMahon et al, 2017).…”