The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1

Maria Buxadé; Josep L Parra; Simon Rousseau; Natalia Shpiro; Rodolfo Marquez; Nick Morrice; Jenny Bain; Enric Espel; Christopher G Proud

doi:10.1016/j.immuni.2005.06.009

The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1

Immunity. 2005 Aug;23(2):177-89. doi: 10.1016/j.immuni.2005.06.009.

Authors

Maria Buxadé¹, Josep L Parra, Simon Rousseau, Natalia Shpiro, Rodolfo Marquez, Nick Morrice, Jenny Bain, Enric Espel, Christopher G Proud

Affiliation

¹ Departament de Fisiologia, Universitat de Barcelona, Spain.

PMID: 16111636
DOI: 10.1016/j.immuni.2005.06.009

Abstract

Posttranscriptional regulatory mechanisms control TNFalpha expression through AU-rich elements in the 3'UTR of its mRNA. This is mediated through Erk and p38 MAP kinase signaling, although the mechanisms involved remain poorly understood. Here, we show that the MAP kinase signal-integrating kinases (Mnks), which are activated by both these pathways, regulate TNFalpha expression in T cells via the 3'UTR. A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNFalpha production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNFalpha 3'UTR. We identify ARE binding proteins that are Mnk substrates, such as hnRNP A1, which they phosphorylate at two sites in vitro. hnRNP A1 is phosphorylated in response to T cell activation, and this is blocked by Mnk inhibition. Moreover, Mnk-mediated phosphorylation decreases binding of hnRNP A1 to TNFalpha-ARE in vitro or TNFalpha-mRNA in vivo. Therefore, Mnks are novel players in cytokine regulation and potential new targets for anti-inflammatory therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / metabolism
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / metabolism
Genes, Reporter
Heterogeneous Nuclear Ribonucleoprotein A1
Heterogeneous-Nuclear Ribonucleoprotein Group A-B / antagonists & inhibitors
Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
Humans
Jurkat Cells
MAP Kinase Signaling System / physiology*
Phosphorylation
Protein Binding / genetics
Protein Binding / immunology
Protein Biosynthesis / physiology
RNA, Messenger / metabolism
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / biosynthesis*
Tumor Necrosis Factor-alpha / genetics
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

3' Untranslated Regions
Heterogeneous Nuclear Ribonucleoprotein A1
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
RNA, Messenger
Tumor Necrosis Factor-alpha
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases