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

Keiko Morimoto; Yoshihiro Baba; Hisaaki Shinohara; Sujin Kang; Satoshi Nojima; Tetsuya Kimura; Daisuke Ito; Yuji Yoshida; Yohei Maeda; Hana Sarashina-Kida; Masayuki Nishide; Takashi Hosokawa; Yasuhiro Kato; Yoshitomo Hayama; Yuhei Kinehara; Tatsusada Okuno; Hyota Takamatsu; Toru Hirano; Yoshihito Shima; Masashi Narazaki; Tomohiro Kurosaki; Toshihiko Toyofuku; Atsushi Kumanogoh

doi:10.1038/srep25738

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

Keiko Morimoto, Yoshihiro Baba, Hisaaki Shinohara, Sujin Kang, Satoshi Nojima, Tetsuya Kimura, Daisuke Ito, Yuji Yoshida, Yohei Maeda, Hana Sarashina-Kida, Masayuki Nishide, Takashi Hosokawa, Yasuhiro Kato, Yoshitomo Hayama, Yuhei Kinehara, Tatsusada Okuno, Hyota Takamatsu, Toru Hirano, Yoshihito Shima, Masashi NarazakiTomohiro Kurosaki, Toshihiko Toyofuku, Atsushi Kumanogoh

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19 Citations (Scopus)

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-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.

Original language	English
Article number	25738
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep25738
Publication status	Published - 2016 May 11
Externally published	Yes

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Morimoto, K., Baba, Y., Shinohara, H., Kang, S., Nojima, S., Kimura, T., Ito, D., Yoshida, Y., Maeda, Y., Sarashina-Kida, H., Nishide, M., Hosokawa, T., Kato, Y., Hayama, Y., Kinehara, Y., Okuno, T., Takamatsu, H., Hirano, T., Shima, Y., ... Kumanogoh, A. (2016). LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. Scientific reports, 6, Article 25738. https://doi.org/10.1038/srep25738

Morimoto, K, Baba, Y, Shinohara, H, Kang, S, Nojima, S, Kimura, T, Ito, D, Yoshida, Y, Maeda, Y, Sarashina-Kida, H, Nishide, M, Hosokawa, T, Kato, Y, Hayama, Y, Kinehara, Y, Okuno, T, Takamatsu, H, Hirano, T, Shima, Y, Narazaki, M, Kurosaki, T, Toyofuku, T & Kumanogoh, A 2016, 'LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation', Scientific reports, vol. 6, 25738. https://doi.org/10.1038/srep25738

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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-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.",

author = "Keiko Morimoto and Yoshihiro Baba and Hisaaki Shinohara and Sujin Kang and Satoshi Nojima and Tetsuya Kimura and Daisuke Ito and Yuji Yoshida and Yohei Maeda and Hana Sarashina-Kida and Masayuki Nishide and Takashi Hosokawa and Yasuhiro Kato and Yoshitomo Hayama and Yuhei Kinehara and Tatsusada Okuno and Hyota Takamatsu and Toru Hirano and Yoshihito Shima and Masashi Narazaki and Tomohiro Kurosaki and Toshihiko Toyofuku and Atsushi Kumanogoh",

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T1 - LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation

AU - Morimoto, Keiko

AU - Baba, Yoshihiro

AU - Shinohara, Hisaaki

AU - Kang, Sujin

AU - Nojima, Satoshi

AU - Kimura, Tetsuya

AU - Ito, Daisuke

AU - Yoshida, Yuji

AU - Maeda, Yohei

AU - Sarashina-Kida, Hana

AU - Nishide, Masayuki

AU - Hosokawa, Takashi

AU - Kato, Yasuhiro

AU - Hayama, Yoshitomo

AU - Kinehara, Yuhei

AU - Okuno, Tatsusada

AU - Takamatsu, Hyota

AU - Hirano, Toru

AU - Shima, Yoshihito

AU - Narazaki, Masashi

AU - Kurosaki, Tomohiro

AU - Toyofuku, Toshihiko

AU - Kumanogoh, Atsushi

PY - 2016/5/11

Y1 - 2016/5/11

N2 - 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.

AB - 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.

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

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