LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-?B 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-?B activation and reduced expression of NF-?B target genes including Bcl-xL, cyclin D2, and NFATc1/?A. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-?B activation. Our results reveal a critical role of LRRK1 in NF-?B signaling in B cells and the humoral immune response.

SUBMITTER: Morimoto K 

PROVIDER: S-EPMC4863158 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature