Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1.
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.
Kojo
Satoshi
S
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Elly
Chris
C
Harada
Yohsuke
Y
Langdon
Wallace Y
WY
Kronenberg
Mitchell
M
Liu
Yun-Cai
YC
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017635:Clonal Anergy; D005699:Galactosylceramides / Q000276:immunology; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; C118387:Cblb protein, mouse; D005699:Galactosylceramides; D016328:NF-kappa B; C493154:alpha-galactosylceramide; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse