Requirement for CARMA1 in antigen receptor-induced NF-kappa B activation and lymphocyte proliferation.
Ligation of antigen receptors (TCR, BCR) on T and B lymphocytes leads to the activation of new transcriptional programs and cell cycle progression. Antigen receptor-mediated activation of NF-kappa B, required for proliferation of B and T cells, is disrupted in T cells lacking PKC theta and in B and T cells lacking Bcl10, a caspase recruitment domain (CARD)-containing adaptor protein. CARMA1 (also called CARD11 and Bimp3), the only lymphocyte-specific member in a family of membrane-associated guanylate kinase (MAGUK) scaffolding proteins that interact with Bcl10 by way of CARD-CARD interactions, is required for TCR-induced NF-kappa B activation in Jurkat T lymphoma cells. Here we show that T cells from mice lacking CARMA1 expression were defective in recruitment of Bcl10 to clustered TCR complexes and lipid rafts, in activation of NF-kappa B, and in induction of IL-2 production. Development of CD5(+) peritoneal B cells was disrupted in these mice, as was B cell proliferation in response to both BCR and CD40 ligation. Serum immunoglobulin levels were also markedly reduced in the mutant mice. Together, these results show that CARMA1 has a central role in antigen receptor signaling that results in activation and proliferation of both B and T lymphocytes.
Egawa
Takeshi
T
Molecular Pathogenesis Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Albrecht
Björn
B
Favier
Benoît
B
Sunshine
Mary-Jean
MJ
Mirchandani
Kanchan
K
O'Brien
William
W
Thome
Margot
M
Littman
Dan R
DR
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D015139:Blotting, Southern; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D002874:Chromosome Mapping; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D051528:Guanylate Kinases; D007136:Immunoglobulins / Q000097:blood; D008565:Membrane Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D007136:Immunoglobulins; D008565:Membrane Proteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases