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

Syed Muhammad Hamid, Mevlut Citir, Erdem Murat Terzi, Ismail Cimen, Zehra Yildirim, Asli Ekin Dogan, Begum Kocaturk, Umut Inci Onat, Moshe Arditi, Christian Weber, Alexis Traynor-Kaplan, Carsten Schultz, Ebru Erbay

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere51462
JournalEMBO Reports
Volume21
Issue number12
DOIs
StatePublished - Dec 3 2020

Keywords

  • ER stress
  • hyperlipidemia
  • mTOR signaling
  • macrophage
  • microRNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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