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

Research output: Contribution to journalArticle

6 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 languageEnglish
Article number25738
JournalScientific reports
Volume6
DOIs
Publication statusPublished - May 11 2016

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Leucine
B-Lymphocytes
Phosphotransferases
Humoral Immunity
Immunoglobulin G
Cyclin D2
Genetic Recombination
Antibody Formation
Immunoglobulins
T-Lymphocytes
Antigens
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Morimoto, K., Baba, Y., Shinohara, H., Kang, S., Nojima, S., Kimura, T., ... Kumanogoh, A. (2016). LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. Scientific reports, 6, [25738]. https://doi.org/10.1038/srep25738

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

In: Scientific reports, Vol. 6, 25738, 11.05.2016.

Research output: Contribution to journalArticle

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
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. / LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. In: Scientific reports. 2016 ; Vol. 6.
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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.",
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AU - Kang, Sujin

AU - Nojima, Satoshi

AU - Kimura, Tetsuya

AU - Ito, Daisuke

AU - Yoshida, Yuji

AU - Maeda, Yohei

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AU - Hosokawa, Takashi

AU - Kato, Yasuhiro

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AU - Okuno, Tatsusada

AU - Takamatsu, Hyota

AU - Hirano, Toru

AU - Shima, Yoshihito

AU - Narazaki, Masashi

AU - Kurosaki, Tomohiro

AU - Toyofuku, Toshihiko

AU - Kumanogoh, Atsushi

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