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

Abstract 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 BM relative to wild-type ( WT ). Immunization of Srpk3-cKO mice with a T lymphocyte-independent type-2 antigen elicited greatly reduced amounts of 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. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. 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. One Sentence Summary SRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses.