LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation

• Published in: Scientific reports 2016-05, Vol.6 (1), p.25738-25738, Article 25738
• Main Authors: Morimoto, Keiko, Baba, Yoshihiro, Shinohara, Hisaaki, Kang, Sujin, Nojima, Satoshi, Kimura, Tetsuya, Ito, Daisuke, Yoshida, Yuji, Maeda, Yohei, Sarashina-Kida, Hana, Nishide, Masayuki, Hosokawa, Takashi, Kato, Yasuhiro, Hayama, Yoshitomo, Kinehara, Yuhei, Okuno, Tatsusada, Takamatsu, Hyota, Hirano, Toru, Shima, Yoshihito, Narazaki, Masashi, Kurosaki, Tomohiro, Toyofuku, Toshihiko, Kumanogoh, Atsushi
• Format: Article
• Language: English
• Subjects: 13/109; 13/95; 38/77; 631/250/2152/2153; 631/250/516/1909; 64/60; 82/1; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep25738

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-x L , 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.