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Contribution of human deneddylase‐1/SENP8 to the mucosal inflammatory response (488.1)
Author(s) -
Curtis Valerie,
Ehrentraut Stefan,
Campbell Eric,
Glover Louise,
Bowers Brittelle,
Bayless Amanda,
Kelly Caleb,
Kominsky Douglas,
Colgan Sean
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.488.1
Subject(s) - neddylation , cullin , nedd8 , transactivation , microbiology and biotechnology , gene knockdown , in vivo , proinflammatory cytokine , biology , inflammation , cancer research , chemistry , immunology , cell culture , ubiquitin , transcription factor , biochemistry , ubiquitin ligase , genetics , gene
Recent work has revealed a central role for neddylation (conjugation of a Nedd8 to proteins) to Cullin‐proteins in the induction of the NFκB (via Cullin‐1) and stabilization of hypoxia‐inducible factor (HIF, via Cullin‐2). Here, we elucidate the role of the human deneddylase‐1 (also called SENP8) in inflammatory responses in vitro / in vivo and define mechanisms for targeting SENP8 in models of inflammation. Human endothelial and epithelial cells exposure to inflammatory stimuli significantly induced the neddylation of Cullin‐1 and increased NFκB transactivation. These responses were nearly completely lost in cells lacking SENP8 via lentiviral knock‐down. Further analysis revealed that HIF‐1α protein was stabilized by LPS exposure in wild‐type cells but not in SENP8 knockdown cells. HIF promoter activity was increased following LPS compared to untreated controls. Pharmacological targeting of neddylation (MLN4924) abrogated NFκB responses, stabilized HIF‐1α protein and activated HIF promoter activity. Likewise, MLN4924 reduced secretion of TNF‐α‐elicited pro‐inflammatory cytokines from endothelial cells. In vivo, the neddylation inhibitor MLN4924 led to increased deneddylated Cullin‐1 in a TNBS colitis model and stabilized HIF while treatment with MLN4924 in a DSS colitis model abrogated disease severity. In conclusion, SENP8 is a proximal regulator of Cullin neddylation and fine‐tunes the inflammatory response in vitro and in vivo. Pharmacological inhibition of Cullin neddylation may provide a viable therapeutic opportunity. Grant Funding Source : Supported by NIH grants DK50189, DK96491 and HL60569.