Blimp-1Deltaexon7: a naturally occurring Blimp-1 deletion mutant with auto-regulatory potential

Blimp-1 is a master regulator of terminal B cell differentiation and plays a pivotal role in various developmental processes. In addition to full length Blimp-1, a Blimp-1 mRNA lacking exon 7 (Blimp-1Δ7) has been described to occur in murine B cells. The activity and function of the mutant mRNA-encoded protein (Blimp-1Δ7), lacking three crucial zinc fingers necessary for DNA interaction, is completely unknown. Since isoforms of other prdm family proteins affect each other's functions, we wondered whether Blimp-1Δ7 still plays a role in B cells, independent of direct DNA binding. In this study, we found that Blimp-1Δ7 is preferentially expressed in naïve CD19⁺ B cells. A fraction of Blimp-1Δ7 migrates to the nucleus, colocalizes with HDAC2 and is found at sites of repressed chromatin, although it does not bind to the Blimp-1 DNA consensus site. Unexpectedly, Blimp-1 and Blimp-1Δ7 homodimerize as well as heterodimerize with each other. Ectopic expression of Blimp-1Δ7 in WEHI 231 cells, a Blimp-1-negative murine lymphoma line, leads to cessation of proliferation and enhancement of apoptosis. Importantly, LPS-induced differentiation is suppressed in the presence of Blimp-1Δ7. This is in agreement with our finding that Blimp-1Δ7 interferes with endogenous Blimp-1 expression. Thus, our data suggest an auto-regulatory mechanism of Blimp-1 activation.