Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs

• Published in: The EMBO journal Vol. 21; no. 23; pp. 6505 - 6514
• Main Authors: Rousseau, Simon, Morrice, Nick, Peggie, Mark, Campbell, David G., Gaestel, Matthias, Cohen, Philip
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2002; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Animals; AU-rich element; Chemokine CXCL2; Enzyme Inhibitors - pharmacology; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; hnRNP; Imidazoles - pharmacology; Intracellular Signaling Peptides and Proteins; LPS; MAPKAP-K2; Mice; Mitogen-Activated Protein Kinases - metabolism; Monokines - genetics; p38 MAP kinase; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdf639

Lipopolysaccharide (LPS) stimulates production of inflammatory mediators, partly by stabilizing [interleukin‐6 (IL‐6), cyclooxygenase 2 (COX‐2)] and/or stimulating translation [tumour necrosis factor‐α (TNF‐α)] of their mRNAs. Such regulation depends on AU‐rich elements (AREs) within the 3′‐untranslated regions and is partially suppressed by SB 203580 (which inhibits SAPK2a/p38). The LPS‐induced production of TNF‐α and IL‐6 is suppressed in MAPKAP‐K2‐deficient mice (a kinase activated by SAPK2a/p38). Here, we identify 18 macrophage proteins that bind to AREs and show that hnRNP A0 is a major substrate for MAPKAP‐K2 in this fraction. MAPKAP‐K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS‐stimulated cells. Phosphorylation was prevented by SB 203580 and suppressed in macrophages derived from MAPKAP‐K2‐deficient mice. The mRNAs encoding TNF‐α, COX‐2 and macrophage inflammatory protein‐2 (MIP‐2) bound to hnRNP A0 in LPS‐stimulated macrophages, an interaction prevented by SB 203580. The LPS‐induced stabilization of MIP‐2 mRNA and production of MIP‐2 protein were abolished when macrophages were incubated with SB 203580 plus PD 184352 (which inhibits the classical MAP kinase cascade). Our data suggest that LPS‐induced binding of hnRNP A0 to AREs may contribute to the post‐transcriptional regulation of specific mRNAs.