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

Christopher Tiedje; Natalia Ronkina; Mohammad Tehrani; Sonam Dhamija; Kathrin Laass; Helmut Holtmann; Alexey Kotlyarov; Matthias Gaestel

doi:10.1371/journal.pgen.1002977

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.

Authors

Christopher Tiedje¹, Natalia Ronkina, Mohammad Tehrani, Sonam Dhamija, Kathrin Laass, Helmut Holtmann, Alexey Kotlyarov, Matthias Gaestel

Affiliation

¹ Institute of Biochemistry, Hannover Medical School, Hannover, Germany.

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

Grants and funding

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.