The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation

PLoS Genet. 2012 Sep;8(9):e1002977. doi: 10.1371/journal.pgen.1002977. Epub 2012 Sep 27.

Abstract

TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU-rich element (ARE) in the TNF mRNA. Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AU Rich Elements / genetics*
  • ELAV Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophages / metabolism
  • Phosphorylation
  • Protein Biosynthesis*
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Stability / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tristetraprolin* / genetics
  • Tristetraprolin* / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • ELAV Proteins
  • Intracellular Signaling Peptides and Proteins
  • Protein Precursors
  • RNA, Messenger
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • tumor necrosis factor precursor
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (DFG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.