title: Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis.
abstract: In a genome-wide ENU mouse mutagenesis screen a recessive mouse mutation, unmodulated, was isolated with profound defects in humoral immune responses, selective deficits in B cell activation by antigen receptors and T cell costimulation by CD28, and gradual development of atopic dermatitis with hyper-IgE. Mutant B cells are specifically defective in forming connections between antigen receptors and two key signaling pathways for immunogenic responses, NF-kappaB and JNK, but signal normally to calcium, NFAT, and ERK. The mutation alters a conserved leucine in the coiled-coil domain of CARMA-1/CARD11, a member of the MAGUK protein family implicated in organizing multimolecular signaling complexes. These results define Carma-1 as a key regulator of the plasticity in antigen receptor signaling that underpins opposing mechanisms of immunity and tolerance.
authors.affiliation: Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, ACT 2601, Canberra, Australia.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Jun
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Wilson
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blery
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Miosge
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Edyta M
authors.initials: EM
authors.lastname: Kucharska
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Heather
authors.initials: H
authors.lastname: Domashenz
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Hong
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.forename: Keats A
authors.initials: KA
authors.lastname: Nelms
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D003872:Dermatitis / Q000276:immunology; D051528:Guanylate Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016328:NF-kappa B; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases