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Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8883-8. doi: 10.1073/pnas.1309218111. Epub 2014 May 30.

The GTPase-activating protein GIT2 protects against colitis by negatively regulating Toll-like receptor signaling.

Author information

1
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China;Beijing Institute of Radiation Medicine, Beijing 100850, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, Beijing 102206, China; and.
2
Beijing Institute of Radiation Medicine, Beijing 100850, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, Beijing 102206, China; and.
3
Beijing Institute of Radiation Medicine, Beijing 100850, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, Beijing 102206, China; andDepartment of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.
4
Beijing Institute of Radiation Medicine, Beijing 100850, China;
5
Beijing Institute of Radiation Medicine, Beijing 100850, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, Beijing 102206, China; and wangjian@bmi.ac.cn xmyang2@bmi.ac.cn hefc@bmi.ac.cn.

Abstract

G protein-coupled receptor kinase-interactor 2 (GIT2) regulates thymocyte positive selection, neutrophil-direction sensing, and cell motility during immune responses by regulating the activity of the small GTPases ADP ribosylation factors (Arfs) and Ras-related C3 botulinum toxin substrate 1 (Rac1). Here, we show that Git2-deficient mice were more susceptible to dextran sodium sulfate (DSS)-induced colitis, Escherichia coli, or endotoxin-shock challenge, and a dramatic increase in proinflammatory cytokines was observed in Git2 knockout mice and macrophages. GIT2 is a previously unidentified negative regulator of Toll-like receptor (TLR)-induced NF-κB signaling. The ubiquitination of TNF receptor associated factor 6 (TRAF6) is critical for the activation of NF-κB. GIT2 terminates TLR-induced NF-κB and MAPK signaling by recruiting the deubiquitinating enzyme Cylindromatosis to inhibit the ubiquitination of TRAF6. Finally, we show that the susceptibility of Git2-deficient mice to DSS-induced colitis depends on TLR signaling. Thus, we show that GIT2 is an essential terminator of TLR signaling and that loss of GIT2 leads to uncontrolled inflammation and severe organ damage.

KEYWORDS:

CYLD; GIT; IBD; TRAF6

PMID:
24879442
PMCID:
PMC4066529
DOI:
10.1073/pnas.1309218111
[Indexed for MEDLINE]
Free PMC Article

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