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-xL, 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.
Highlights
B cells play central roles in humoral immune responses
We discovered that Leucine-rich repeat kinase 1 (LRRK1) plays a critical role in B-cell development and antibody production by regulating NF-κB signaling
Our findings that LRRK1 interacts with CARMA1 and positively modulates CARMA1-dependent NF-κB activation provide clues about how LRRK1 contributes to NF-κB signaling
Summary
B cells play central roles in humoral immune responses. Antibodies resulting from B cell activation serve to eliminate pathogens and thereby protect the host from viral, bacterial, and parasitic infections[1]. NF-κB plays a crucial role in humoral immunity through a variety of BCR-mediated responses including B-cell activation, proliferation, survival, and effector functions[7]. BCR-induced NF-κB activation is governed by the CBM complex, which contains CARMA1 (caspase recruitment domain, CARD, membrane-associated guanylate kinase, MAGUK, protein 1), BCL10 (B-cell lymphoma 10), and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1)[12]. Formation of this complex is triggered by phosphorylation of CARMA1 by protein kinase C-β(PKC-β), which allows CARMA1 to recruit BCL10 and MALT1 into cellular membranes[13]. LRRK1 has been shown to have a wide variety of functions and be expressed predominantly in B cells and monocytes in human peripheral blood[23], its contribution to the immune system remains to be determined
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