Kojo Satoshi, Elly Chris, Harada Yohsuke, Langdon Wallace Y, Kronenberg Mitchell, Liu Yun-Cai
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17847-51. doi: 10.1073/pnas.0904078106. Epub 2009 Oct 7.
Repeated injection of alpha-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-gamma 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 NFkappaB 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-gamma production. The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFkappaB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy.
重复注射α-半乳糖神经酰胺（一种自然杀伤T细胞（NKT细胞）的激动性配体）会导致长期无反应性或失能，这严重限制了其临床应用。然而，导致NKT细胞失能诱导的分子机制仍不清楚。我们在此表明，Cbl-b缺陷可挽救失能NKT细胞中观察到的干扰素-γ产生减少和肿瘤排斥失败的情况。正如Cbl-b(-/-)与其环指突变体NKT细胞之间的相似性所揭示的那样，Cbl-b E3连接酶活性对于失能诱导至关重要。Cbl-b与CARMA1结合并促进其单泛素化，CARMA1是NFκB激活中的关键信号分子。与CARMA1的泛素缀合会破坏其与Bcl10的复合物形成，而不影响其蛋白质稳定性。此外，CARMA1(-/-) NKT细胞在干扰素-γ产生方面存在缺陷。该研究确定了一条重要的信号通路，该通路将Cbl-b诱导的单泛素化与NKT细胞失能诱导中的NFκB激活联系起来，这可能有助于设计人类癌症治疗方法。
