SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses

Nathan D. Mathewson, Hideaki Fujiwara, Shin Rong Wu, Tomomi Toubai, Katherine Oravecz-Wilson, Yaping Sun, Corinne Rossi, Cynthia Zajac, Yi Sun, Pavan Reddy

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5 Citations (Scopus)

Abstract

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-κB 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 T-cell–mediated immunopathologies, such as graft-versus-host disease.

Original languageEnglish
Pages (from-to)2679-2691
Number of pages13
JournalAmerican Journal of Pathology
Volume186
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Mathewson, N. D., Fujiwara, H., Wu, S. R., Toubai, T., Oravecz-Wilson, K., Sun, Y., Rossi, C., Zajac, C., Sun, Y., & Reddy, P. (2016). SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses. American Journal of Pathology, 186(10), 2679-2691. https://doi.org/10.1016/j.ajpath.2016.06.014