Interferon-γ inhibits sirtuin 6 gene expression in intestinal epithelial cells through a microRNA-92b-dependent mechanism

Fangyi Liu, Xiao Wang, Hua Geng, Heng Fu Bu, Peng Wang, Isabelle G. de Plaen, Hong Yang, Jiaming Qian, Xiao Di Tan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Sirtuin 6 (Sirt6) is predominantly expressed in epithelial cells in intestinal crypts. It plays an important role in protecting intestinal epithelial cells against inflammatory injury. Previously, we found that colitis is associated with the downregulation of Sirt6 protein in the intestines. Here, we report that murine interferon-γ (Ifnγ) inhibits Sirt6 protein but not mRNA expression in young adult mouse colonocytes (YAMC, a mouse colonic epithelial cell line) in a dose- and time-dependent manner. Using microRNA array analysis, we showed that Ifnγ induces expression of miR-92b in YAMC cells. With in silico analysis, we found that the Sirt6 3=-untranslated region (UTR) contains a putative binding site for miR-92b. Luciferase assay showed that Ifnγ inhibited Sirt6 3=-UTR activity and this effect was mimicked by miR-92b via directly targeting the miR-92b seed site in the 3=-UTR of Sirt6 mRNA. Furthermore, Western blot demonstrated that miR-92b downregulated Sirt6 protein expression in YAMC cells. Blocking miR-92b with a specific inhibitor attenuated the inhibitory effect of Ifnγ on Sirt6 protein expression in the cells. Collectively, our data suggest that Ifnγ inhibits Sirt6 protein expression in intestinal epithelial cells via a miR-92b-mediated mechanism. miR-92b may be a novel therapeutic target for rescuing Sirt6 protein levels in intestinal epithelial cells, thereby protecting against intestinal mucosal injury caused by inflammation.

Original languageEnglish (US)
Pages (from-to)C732-C739
JournalAmerican Journal of Physiology - Cell Physiology
Volume318
Issue number4
DOIs
StatePublished - Apr 2020

Keywords

  • Cell signaling
  • Gene expression
  • Inflammation
  • Intestinal epithelial cells
  • MicroRNAs

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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