title: LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.
abstract: B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1(-/-) mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.|Department of Clinical Application of Biologics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.|Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.|Department of Geriatric Medicine and Nephrology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.|Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Hana
authors.initials: H
authors.lastname: Sarashina-Kida
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishide
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosokawa
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Hayama
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kinehara
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narazaki
authors.affiliation: Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Department of Immunology and Regenerative Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.affiliation: Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000378:metabolism; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D007074:Immunoglobulin G; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C585046:Lrrk1 protein, mouse; D017346:Protein Serine-Threonine Kinases