Protein phosphatase 2A (PP2A) is increased in old murine B cells and mediates p38 MAPK/tristetraprolin dephosphorylation and E47 mRNA instability

摘要

The transcription factor E47, which regulates immunoglobulin class switch in murine splenic B cells, is down-regulated in aged B cells due to reduced mRNA stability. Part of the decreased stability of E47 mRNA is mediated by tristetraprolin (TTP), a physiological regulator of mRNA stability. We have previously shown that TTP mRNA and protein expression are higher in old B cells, and the protein is less phosphorylated in old B cells, both of which lead to more binding of TTP to the 3’-UTR of E47 mRNA, thereby decreasing its stability. PP2A is a protein phosphatase that plays an important role in the regulation of a number of major signaling pathways. Herein we show that not only the amount but also the activity of PP2A is increased in old B cells. As a consequence of this higher phosphatase activity in old B cells, p38 MAPK and TTP (either directly or indirectly by PP2A) are less phosphorylated as compared with young B cells. PP2A dephosphorylation of p38 MAPK and/or TTP likely generates more binding of the hypophosphorylated TTP to the E47 mRNA, inducing its degradation. This mechanism may be at least in part responsible for the age-related decrease in class switch.