TY - JOUR
T1 - Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1
AU - Kojo, Satoshi
AU - Elly, Chris
AU - Harada, Yohsuke
AU - Langdon, Wallace Y.
AU - Kronenberg, Mitchell
AU - Liu, Yun Cai
PY - 2009/10/20
Y1 - 2009/10/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70449555955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70449555955&partnerID=8YFLogxK
U2 - 10.1073/pnas.0904078106
DO - 10.1073/pnas.0904078106
M3 - Article
C2 - 19815501
AN - SCOPUS:70449555955
SN - 0027-8424
VL - 106
SP - 17847
EP - 17851
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -
