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

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      Embargo Lift Date: 2021-05-02
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      Author(s)
      Hamid, S. M.
      Çıtır, M.
      Terzi, E. M.
      Çimen, İ.
      Yıldırım, Zehra
      Doğan, Aslı Ekin
      Kocatürk, B.
      Onat, Umut Inci
      Arditi, M.
      Weber, C.
      Traynor‐Kaplan, A.
      Schultz, C.
      Erbay, E.
      Date
      2020-11
      Source Title
      EMBO Reports
      Print ISSN
      1469-221X
      Publisher
      Wiley-VCH Verlag
      Volume
      21
      Issue
      12
      Pages
      e51462
      Language
      English
      Type
      Article
      Item Usage Stats
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      164
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      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.
      Keywords
      ER stress
      MicroRNA
      mTOR signaling
      Hyperlipidemia
      Macrophage
      Signal transduction
      RNA
      Molecular biology of disease
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      http://hdl.handle.net/11693/75652
      Published Version (Please cite this version)
      https://dx.doi.org/10.15252/embr.202051462
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      • Department of Molecular Biology and Genetics 542
      • Nanotechnology Research Center (NANOTAM) 1179
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