Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1

Satoshi Kojo, Chris Elly, Yohsuke Harada, Wallace Y. Langdon, Mitchell Kronenberg, Yun Cai Liu

研究成果: Contribution to journalArticle査読

52 被引用数 (Scopus)


Repeated injection of α-galactosylceramide, an agonistic ligand for natural killer T (NKT) cells, results in long-term unresponsiveness or anergy, which severely limits its clinical application. However, the molecular mechanisms leading to NKT anergy induction remain unclear. We show here that the decreased IFN-γ production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b E3 ligase activity is critical for the anergy induction, as revealed by the similarity between Cbl-b-/- and its RING finger mutant NKT cells. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFκB activation. Ubiquitin conjugation to CARMA1 disrupts its complex formation with Bcl10 without affecting its protein stability. In addition, CARMA1-/- NKT cells are defective in IFN-γ production. The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFκB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy.

ジャーナルProceedings of the National Academy of Sciences of the United States of America
出版ステータス出版済み - 10 20 2009

All Science Journal Classification (ASJC) codes

  • General

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