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)
The production of high-affinity antibodies by B cells is essential for the clearance of pathogens. Increased antibody affinity for antigen is achieved by the process of affinity maturation in germinal centres (GCs). This is an iterative process in which B cells re-cycle between proliferation and the acquisition of mutations and antigen-based positive selection of the highest-affinity B cell clones. The post-transcriptional regulator microRNA (miR)-155 is critical for efficient affinity maturation and the maintenance of the GCs.
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.
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.