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

Hamid S. M., Citir M., Terzi E. M., Cimen I., Yildirim Z., Dogan A. E., ...Daha Fazla

EMBO REPORTS, cilt.21, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 21
  • Basım Tarihi: 2020
  • Doi Numarası: 10.15252/embr.202051462
  • Dergi Adı: EMBO REPORTS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Agricultural & Environmental Science Database, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: ER stress, microRNA, mTOR signaling, hyperlipidemia, macrophage, ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, ER STRESS, HEPATIC STEATOSIS, MICRORNA TARGETS, PATHWAY, CELL, METABOLISM, MTOR, ATHEROSCLEROSIS
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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/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.