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The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells.

Abstract
The type 1 diabetes (T1D) risk locus on chromosome 15q25.1 harbors the candidate gene CTSH (cathepsin H). We previously demonstrated that CTSH regulates β-cell function in vitro and in vivo. CTSH overexpression protected insulin-secreting INS-1 cells against cytokine-induced apoptosis. The purpose of the present study was to identify the genes through which CTSH mediates its protective effects. Microarray analysis identified 63 annotated genes differentially expressed between CTSH-overexpressing INS-1 cells and control cells treated with interleukin-1β and interferon-γ for up to 16h. Permutation test identified 10 significant genes across all time-points: Elmod1, Fam49a, Gas7, Gna15, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified the "Inflammation mediated by chemokine and cytokine signaling pathway" with Gna15, Ptgs1 and Rac2 as significant. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis, suggesting that the small GTPase and T1D candidate gene Rac2 contributes to the anti-apoptotic effect of CTSH.
AuthorsTina Fløyel, Aashiq Hussain Mirza, Simranjeet Kaur, Caroline Frørup, Reza Yarani, Joachim Størling, Flemming Pociot
JournalMolecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 518 Pg. 110993 (12 01 2020) ISSN: 1872-8057 [Electronic] Ireland
PMID32814070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Cytokines
  • Cathepsin H
  • rac GTP-Binding Proteins
Topics
  • Animals
  • Apoptosis (drug effects, genetics)
  • Cathepsin H (genetics, physiology)
  • Cells, Cultured
  • Cytokines (pharmacology)
  • Cytoprotection (drug effects, genetics)
  • Humans
  • Insulin-Secreting Cells (drug effects, physiology)
  • Mice
  • Rats
  • rac GTP-Binding Proteins (physiology)
  • RAC2 GTP-Binding Protein

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