SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo. Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO mouse bone marrow relative to wild-type (WT). Immunization of Srpk3-cKO mice with the T lymphocyte-independent type-2 antigen 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) elicited greatly reduced amounts of NP-specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. We conclude that SRPK3 is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells.