Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth. (2nd November 2020)

• Record Type: Journal Article
• Authors: Hamid, Syed Muhammad; Citir, Mevlut; Terzi, Erdem Murat; Cimen, Ismail; Yildirim, Zehra; Dogan, Asli Ekin; Kocaturk, Begum; Onat, Umut Inci; Arditi, Moshe; Weber, Christian; Traynor‐Kaplan, Alexis; Schultz, Carsten; Erbay, Ebru
• Is Part Of: EMBO reports. Volume 21:Number 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-02
• Subjects: ER stress -- microRNA -- mTOR signaling -- hyperlipidemia -- macrophage; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051462
• Languages: English
• ISSNs: 1469-221X

Abstract

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 box‐binding 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)P3 ) 5‐phosphatase‐2 (INPPL1) is a direct target of miR‐2137, which controls PI(3, 4, 5)P3 levels in macrophages. The modulation of cellular PI(3, 4, 5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1‐induced miR‐2137 demonstrates how the ER can provide a critical input into cell growth decisions. Synopsis: miR‐2137 is a new RNA substrate of IRE1, the master regulator of the Unfolded Protein Response, and connects IRE1 to phosphatidylinositide‐derived signaling lipid metabolism and growth signaling. Endoplasmic reticulum‐anchored IRE1's endoribonuclease activity leads to maturation of a micro RNA, miR‐2137. IRE1 plays an unprecedented role in regulating the metabolism of phosphatidylinositide‐derived signaling lipids in macrophages. miR‐2137 is induced by high fat diet‐activated IRE1 in lipid‐laden, foamy macrophages that are found in atherosclerotic plaques and is blocked by an IRE1 endoribonuclease‐specific inhibitor, suggesting miR‐2137 could be a mediator of macrophage IRE1's known pro‐atherogenic action. Abstract : miR‐2137 is a new RNA substrate of IRE1, the master regulator of the Unfolded Protein Response, and connects IRE1 to phosphatidylinositide‐derived signaling lipid metabolism and growth signaling.