Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses

Valerie F. Curtis, Stefan F. Ehrentraut, Eric L. Campbell, Louise E. Glover, Amanda J. Bayless, Caleb J. Kelly, Douglas J. Kominsky, Sean P. Colgan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

There is interest in understanding post-translational modifications of proteins in inflammatory disease. Neddylation is the conjugation of the molecule neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to promote protein stabilization. Cullins are a family of NEDD8 targets important in the stabilization and degradation of proteins, such as hypoxia-inducible factor (HIF; via Cullin-2). Here, we elucidate the role of human deneddylase-1 (DEN-1, also called SENP8) in inflammatory responses in vitro and in vivo and define conditions for targeting neddylation in models of mucosal inflammation. HIF provides protection in inflammatory models, so we examined the contribution of DEN-1 to HIF stabilization. Pharmacologic targeting of neddylation activity with MLN4924 (IC50, 4.7 nM) stabilized HIF-1α, activated HIF promoter activity by 2.5-fold, and induced HIF-target genes in human epithelial cells up to 5-fold. Knockdown of DEN-1 in human intestinal epithelial cells resulted in increased kinetics in barrier formation, decreased permeability, and enhanced barrier restitution by 2 ± 0.5-fold. Parallel studies in vivo revealed that MLN4924 abrogated disease severity in murine dextran sulfate sodium colitis, including weight loss, colon length, and histologic severity. We conclude that DEN-1 is a regulator of cullin neddylation and fine-tunes the inflammatory response in vitro and in vivo. Pharmacologic inhibition of cullin neddylation may provide a therapeutic opportunity in mucosal inflammatory disease.

Original languageEnglish
Pages (from-to)208-215
JournalThe FASEB Journal
Volume29
Issue number1
Early online date17 Oct 2014
DOIs
Publication statusPublished - 01 Jan 2015
Externally publishedYes

Keywords

  • Hypoxia
  • Inflammation
  • Intestinal epithelia

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses'. Together they form a unique fingerprint.

Cite this