Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling.
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.
Cao
Wangsen
W
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. wcao@jhmi.edu
Bao
Clare
C
Padalko
Elizaveta
E
Lowenstein
Charles J
CJ
D000107:Acetylation; D000818:Animals; D015152:Blotting, Northern; D002087:Butyrates / Q000494:pharmacology; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D009573:Nitrites; D051193:Toll-Like Receptors; C012589:trichostatin A; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse