Tristetraprolin down‐regulates E47 mRNA stability in old splenic murine B cells

Abstract

The E2A‐encoded transcription factor E47, which regulates class switch recombination (CSR) in splenic B cells, is down‐regulated in aged murine B cells, due to increased E47 mRNA decay. We have previously shown that part of the decreasedstability of E47 mRNA seen in aged B cells is mediated by tristetraprolin, TTP, which binds AU‐rich elements in the 3′‐untranslated region (3′‐UTR) of mRNAs leading to their rapid degradation. Levels of TTP are higher and phosphorylation of TTP is lower in old B cells than in young B cells, generating more mRNA degradation. The pro‐B cell line 107.2 transfected with the TTP‐siRNA suppressed TTP and led to enhancedaccumulation of E47 mRNA. These results altogether suggest that TTP plays a relevant role in the degradation of E47 mRNA and in the control of CSR and somatic hypermutation of Ig, critical for high affinity Ig and optimal response to pathogens. We have also introduced the coding region of E47 (lacking the 3′‐UTR) by retroviral transduction of young and old splenic activated B cells. This over‐expression of E47 up‐regulated activation‐induced cytidine deaminase and CSR in both young and old, restoring the old levels to that of normal young levels.This work is supported by NIH AG‐17618, AG‐23717 (BBB) and AG025256 and AI064591 (RLR)