The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1.
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.
Buxadé
Maria
M
Departament de Fisiologia, Universitat de Barcelona, Spain.
Parra
Josep L
JL
Rousseau
Simon
S
Shpiro
Natalia
N
Marquez
Rodolfo
R
Morrice
Nick
N
Bain
Jenny
J
Espel
Enric
E
Proud
Christopher G
CG
D020413:3' Untranslated Regions / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D020413:3' Untranslated Regions; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases