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

Buxade, M., Parra, J.L., Rousseau, S., Shpiro, N., Marquez, R., Morrice, N., Bain, J., Espel, E. and Proud, C.G. (2005) The Mnks are novel components in the control of TNF? biosynthesis and phosphorylate and regulate hnRNP A1. Immunity, 23 (2), 177-189. (doi:10.1016/j.immuni.2005.06.009).

Abstract

Posttranscriptional regulatory mechanisms control TNF alpha 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 TNFa expression in T cells via the 3'UTR. A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNFa production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNFa 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 TNF alpha-ARE in vitro or TNF alpha-mRNA in vivo. Therefore, Mnks are novel players in cytokine regulation and potential new targets for antiinflammatory therapy.

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