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Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth
Author(s) -
Hamid Syed Muhammad,
Citir Mevlut,
Terzi Erdem Murat,
Cimen Ismail,
Yildirim Zehra,
Dogan Asli Ekin,
Kocaturk Begum,
Onat Umut Inci,
Arditi Moshe,
Weber Christian,
TraynorKaplan Alexis,
Schultz Carsten,
Erbay Ebru
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051462
Subject(s) - inositol , enzyme , macrophage , microbiology and biotechnology , signal transduction , biochemistry , biology , chemistry , receptor , in vitro
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)P 3 ) 5‐phosphatase‐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 IRE1‐induced miR‐2137 demonstrates how the ER can provide a critical input into cell growth decisions.