Novel unconventional myosins in B cell homeostasis

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ABSTRACT Incurable autoimmune diseases afflict millions of Americans, cause pain and persistent damage to multiple organ systems, and have a major impact on patient health, well-being and quality of life. Increased B cell numbers, greater B cell activation and differentiation into plasma cells, and autoantibody production often characterize autoimmunity, signifying that dysregulated B cell survival and differentiation are critical steps in autoimmune pathogenesis. Identification of proteins and molecular events that regulate B cell survival, activation and differentiation is therefore critical for better mechanistic understanding of autoimmune disease development. Myo18A is a scaffolding protein with a unique domain organization that enables assembly of multiprotein complexes in various subcellular compartments of non-immune cells. We reported that B cells express Myo18A, and that its conditional deletion in B cells (Myo18A BKO) leads to an increase in mature B cells and plasma cells, splenomegaly, hypergammaglobulinemia, and development of autoantibodies. Interestingly, this profile overlaps with autoimmune manifestations reported in transgenic mice overexpressing the B cell survival factor BAFF, and in mice with genetic deletion of proteins involved in mRNA decay. In preliminary data, we observed that Myo18A-deficient B cells display features of greater BAFF responsiveness, including increased mitochondrial size and gene expression, and stronger pro-survival Akt signaling, indicating that Myo18A negatively regulates B cell response to BAFF. Additionally, deletion of Myo18A in B cells increased the basal expression and reduced the decay of mRNA encoding Blimp-1, a key transcription factor in B cell differentiation. Further, Myo18A in B cells bound to Blimp1 mRNA and co-localized with subcellular mRNA degradation sites, indicating that Myo18A is involved in post-transcriptional regulation and expression of Blimp- 1. Our published and preliminary data suggest that Myo18A is an important and previously unrecognized determinant in B cell immunity. Our specific aims are to test the hypotheses that (1) Myo18A restricts BCR and BAFF-R signaling to control B cell homeostasis, (2) Myo18A inhibits mRNA stability to inform B cell gene expression, and (3) Myo18A limits B cell differentiation by controlling the B cell transcriptome. The proposed research is innovative because it will establish a novel role for the unconventional myosin family protein Myo18A in preventing uncontrolled B cell activation and differentiation. Specifically, our research will identify a novel functional connection between Myo18A and B cell survival and differentiation through regulation of B cell antigen and BAFF responsiveness and post-transcriptional mRNA stability. This research is expected to have significant impact because it will enable better mechanistic understanding of the molecular processes that prevent exaggerated antibody development.