期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 10, 页码 2679-2691出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.06.014
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资金
- NIH National Heart, Lung, and Blood Institute [HL-090775, HL-128046]
- National Cancer Institute [CA-173878, CA-171277]
- University of Michigan Cancer Center (NIH) [CA46592]
- University of Michigan Gut Peptide Research Center (NIH) [DK34933]
Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell mediated immunity using multiple approaches: a novel T-cell specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development. However, in vitro stimulation of KO T cells revealed significantly decreased activation, proliferation, and T-effector cytokine release, compared with WT. Using in vivo clinically relevant models of allogeneic bone marrow transplantation also demonstrated reduced proliferation and effector cytokine secretion associated with markedly reduced graft-versus-host disease. Similar in vitro and in vivo results were observed with the small-molecule inhibitor of neddylation, MLN4924. Mechanistic studies demonstrated that SAG-mediated effects in T cells were concomitant with an increase in suppressor of cytokine signaling, but not NF-kappa B translocation. Our studies suggest that SAG is a novel molecular target that regulates T-cell responses and that inhibiting neddylation with the clinically available small-molecule MLN4924 may represent a novel strategy to mitigate I-cell mediated immunopathologies, such as graft-versus host disease.
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