title: Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-κB signalling.
abstract: CARMA1-mediated NF-κB activation controls lymphocyte activation through antigen receptors and survival of some malignant lymphomas. CARMA1 clusters are formed on physiological receptor-mediated activation or by its oncogenic mutation in activated B-cell-diffuse large B-cell lymphomas (ABC-DLBCLs) with constitutive NF-κB activation. However, regulatory mechanisms and relevance of CARMA1 clusters in the NF-κB pathway are unclear. Here we show that SH3 and GUK domain interactions of CARMA1 link CARMA1 clustering to signal activation. SH3 and GUK domains of CARMA1 interact by either intra- or intermolecular mechanisms, which are required for activation-induced assembly of CARMA1. Disruption of these interactions abolishes the formation of CARMA1 microclusters at the immunological synapse, CARMA-regulated signal activation following antigen receptor stimulation as well as spontaneous CARMA1 clustering and NF-κB activation by the oncogenic CARMA1 mutation in ABC-DLBCLs. Thus, the SH3-GUK interactions that regulate CARMA1 cluster formations are promising therapeutic targets for ABC-DLBCLs.
authors.affiliation: 1] Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan [2] Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.affiliation: 1] Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan [2] PRESTO, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yokosuka
authors.affiliation: Laboratory of Plant Genome Informatics, Department of Plant Genome Research, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirakawa
authors.affiliation: PRESTO, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Ishihara
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasukawa
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000096:biosynthesis* / Q000737:chemistry; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D006162:Guanylate Cyclase / Q000096:biosynthesis* / Q000737:chemistry; D051528:Guanylate Kinases / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D007107:Immune System / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000737:chemistry; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C073701:Nfkb1 protein, mouse; D051528:Guanylate Kinases; C426242:CARD11 protein, human; D006162:Guanylate Cyclase