PMID- 33140520
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20221005
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 21
IP  - 12
DP  - 2020 Dec 3
TI  - Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and 
      macrophage growth.
PG  - e51462
LID - 10.15252/embr.202051462 [doi]
LID - e51462
AB  - 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.
CI  - (c) 2020 The Authors.
FAU - Hamid, Syed Muhammad
AU  - Hamid SM
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
FAU - Citir, Mevlut
AU  - Citir M
AD  - The Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 
      Heidelberg, Germany.
FAU - Terzi, Erdem Murat
AU  - Terzi EM
AD  - Department of Pathology, Laura & Isaac Perlmutter Cancer Center, New York 
      University School of Medicine, New York, NY, USA.
FAU - Cimen, Ismail
AU  - Cimen I
AUID- ORCID: 0000-0002-8182-6968
AD  - Institute for Cardiovascular Prevention, LMU Munich, German Cardiovascular 
      Research Centre, partner site Munich Heart Alliance Munich, Munich, Germany.
FAU - Yildirim, Zehra
AU  - Yildirim Z
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
AD  - Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
AD  - National Nanotechnology Center, Bilkent University, Ankara, Turkey.
FAU - Dogan, Asli Ekin
AU  - Dogan AE
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
AD  - Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
AD  - National Nanotechnology Center, Bilkent University, Ankara, Turkey.
FAU - Kocaturk, Begum
AU  - Kocaturk B
AUID- ORCID: 0000-0003-3657-6055
AD  - Department of Pediatrics and Medicine, Division of Infectious Diseases and 
      Immunology, and Infectious and Immunologic Diseases Research Center, Department 
      of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
FAU - Onat, Umut Inci
AU  - Onat UI
AD  - Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
AD  - National Nanotechnology Center, Bilkent University, Ankara, Turkey.
FAU - Arditi, Moshe
AU  - Arditi M
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
AD  - Department of Pediatrics and Medicine, Division of Infectious Diseases and 
      Immunology, and Infectious and Immunologic Diseases Research Center, Department 
      of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
AD  - Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 
      USA.
FAU - Weber, Christian
AU  - Weber C
AUID- ORCID: 0000-0003-4610-8714
AD  - Institute for Cardiovascular Prevention, LMU Munich, German Cardiovascular 
      Research Centre, partner site Munich Heart Alliance Munich, Munich, Germany.
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands.
AD  - Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
FAU - Traynor-Kaplan, Alexis
AU  - Traynor-Kaplan A
AD  - Department of Medicine, University of Washington School of Medicine, Seattle, WA, 
      USA.
AD  - ATK Innovation, Analytics and Discovery, North Bend, WA, USA.
FAU - Schultz, Carsten
AU  - Schultz C
AUID- ORCID: 0000-0002-5824-2171
AD  - The Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 
      Heidelberg, Germany.
AD  - Department of Chemical Physiology and Biochemistry, Oregon Health & Science 
      University, Portland, OR, USA.
FAU - Erbay, Ebru
AU  - Erbay E
AUID- ORCID: 0000-0001-9584-1803
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
AD  - Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 
      USA.
LA  - eng
GR  - FY-2017-TR-PD-01/Fulbright Association (FULBRIGHT)/
GR  - 336643/FP7 Ideas: European Research Council (FP7 Ideas)/
GR  - 692511/FP7 Ideas: European Research Council (FP7 Ideas)/
GR  - SFB 1123/Deutsche Forschungsgemeinschaft (DFG)/
GR  - TRR 267-A02/Deutsche Forschungsgemeinschaft (DFG)/
GR  - DFG Transregio 83/Deutsche Forschungsgemeinschaft (DFG)/
GR  - DFG Transregio 86/Deutsche Forschungsgemeinschaft (DFG)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201102
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - 0 (Phosphatidylinositols)
RN  - 4L6452S749 (Inositol)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
CIN - EMBO Rep. 2020 Dec 3;21(12):e51929. PMID: 33274581
MH  - *Endoplasmic Reticulum Stress
MH  - Endoribonucleases/genetics/metabolism
MH  - Humans
MH  - Inositol
MH  - Macrophages/metabolism
MH  - *Phosphatidylinositols
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Unfolded Protein Response
PMC - PMC7726810
OTO - NOTNLM
OT  - ER stress
OT  - hyperlipidemia
OT  - mTOR signaling
OT  - macrophage
OT  - microRNA
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/11/04 06:00
MHDA- 2021/04/28 06:00
PMCR- 2021/12/03
CRDT- 2020/11/03 05:51
PHST- 2020/08/04 00:00 [received]
PHST- 2020/09/19 00:00 [revised]
PHST- 2020/09/22 00:00 [accepted]
PHST- 2020/11/04 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2020/11/03 05:51 [entrez]
PHST- 2021/12/03 00:00 [pmc-release]
AID - EMBR202051462 [pii]
AID - 10.15252/embr.202051462 [doi]
PST - ppublish
SO  - EMBO Rep. 2020 Dec 3;21(12):e51462. doi: 10.15252/embr.202051462. Epub 2020 Nov 
      2.