Lrrk1 Is Critical In The Regulation Of B-Cell Responses And Carma1-Dependent Nf-Kappa B Activation

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-kappa B activation and reduced expression of NF-kappa B target genes including Bcl-x(L), cyclin D2, and NFATc1/alpha A. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-kappa B activation. Our results reveal a critical role of LRRK1 in NF-kappa B signaling in B cells and the humoral immune response.