Final Report Summary - 3W-RGB (Identification of whether, in which aspects and by which function, a RNA binding protein, KH-type splicing regulatory protein governs development and function of B cell, a type of white blood cell)
We first focused on the function of the miR processing protein KSRP in the regulation of B cell function via its effect on miR-155. However we concluded that KSRP does not play a major role in GC-B cells based on experiments using KSRP-deficient mice and therefore shifted the miR-155 itself rather than the miR-155 processing protein.
In order to understand the cellular and molecular mechanism by which miR-155 regulates GC responses, we utilised a miR-155 reporter mouse strain and showed that miR-155 is co-expressed with the proto-oncogene c-Myc in positively-selected B cells. Functionally, miR-155 protects c-Myc+ positively-selected B cells from apoptosis allowing their clonal expansion, which explains why deletion of miR-155 results in impaired affinity maturation and the premature collapse of GCs. Molecularly, miR-155 directly inhibits the Jumonji family member Jarid2, which we identify here as a novel component in the GC response, to promote GC-B cell survival. Our findings also suggest a basis for cooperation between c-Myc and miR-155 during the normal GC response, which may explain a longstanding enigma of how c-Myc and miR-155 can collaboratively function as oncogenes.