Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

Wangsen Cao, Clare Bao, Elizaveta Padalko, Charles J. Lowenstein

Research output: Contribution to journalArticle

Abstract

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in Toll-like receptor (TLR) signaling. MAPK phosphatase-1 (MKP-1) inhibits the MAPK pathway and decreases TLR signaling, but the regulation of MKP-1 is not completely understood. We now show that MKP-1 is acetylated, and that acetylation regulates its ability to interact with its substrates and deactivate inflammatory signaling. We found that LPS activates acetylation of MKP-1. MKP-1 is acetylated by p300 on lysine residue K57 within its substrate-binding domain. Acetylation of MKP-1 enhances its interaction with p38, thereby increasing its phosphatase activity and interrupting MAPK signaling. Inhibition of deacetylases increases MKP-1 acetylation and blocks MAPK signaling in wild-type (WT) cells; however, deacetylase inhibitors have no effect in cells lacking MKP-1. Furthermore, histone deacetylase inhibitors reduce inflammation and mortality in WT mice treated with LPS, but fail to protect MKP-1 knockout mice. Our data suggest that acetylation of MKP-1 inhibits innate immune signaling. This pathway may be an important therapeutic target in the treatment of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)1491-1503
Number of pages13
JournalJournal of Experimental Medicine
Volume205
Issue number6
DOIs
StatePublished - Jun 9 2008

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Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Toll-Like Receptors
Acetylation
Mitogen-Activated Protein Kinases
Histone Deacetylase Inhibitors
Phosphoric Monoester Hydrolases
Knockout Mice
Lysine

ASJC Scopus subject areas

  • Immunology

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Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. / Cao, Wangsen; Bao, Clare; Padalko, Elizaveta; Lowenstein, Charles J.

In: Journal of Experimental Medicine, Vol. 205, No. 6, 09.06.2008, p. 1491-1503.

Research output: Contribution to journalArticle

Cao, Wangsen ; Bao, Clare ; Padalko, Elizaveta ; Lowenstein, Charles J. / Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. In: Journal of Experimental Medicine. 2008 ; Vol. 205, No. 6. pp. 1491-1503.
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