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Review
. 2008 Oct 14;1(41):pe44.
doi: 10.1126/scisignal.141pe44.

Acetylation of MKP-1 and the control of inflammation

Hongbo Chi  1 , Richard A Flavell
Affiliations
Review

Acetylation of MKP-1 and the control of inflammation

Hongbo Chi et al. Sci Signal. .

Abstract

Innate immune responses mediated by Toll-like receptors (TLRs), a class of pattern-recognition receptors, play a critical role in the defense against microbial pathogens. However, excessive TLR-mediated responses result in sepsis, autoimmunity, and chronic inflammation. To prevent deleterious activation of TLRs, cells have evolved multiple mechanisms that inhibit innate immune reactions. Stimulation of TLRs induces the expression of the gene encoding the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), a nuclear-localized dual-specificity phosphatase that preferentially dephosphorylates p38 MAPK and c-Jun N-terminal kinase (JNK), resulting in the attenuation of TLR-triggered production of proinflammatory cytokines. MKP-1 is posttranslationally modified by multiple mechanisms, including phosphorylation. A study now demonstrates that MKP-1 is also acetylated on a key lysine residue following stimulation of TLRs. Acetylation of MKP-1 promotes the interaction of MKP-1 with its substrate p38 MAPK, which results in dephosphorylation of p38 MAPK and the inhibition of innate immunity.

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Figures

Fig. 1
Fig. 1
Multiple layers of regulation of MKP-1. (A) At the transcriptional level, TLR signaling induces MKP-1 expression as a feedback mechanism to switch off MAPK activation, and immunosuppressive agents, such as glucocorticoids and IL-10, induce the expression of MKP-1 to mediate their inhibitory effects on the activation of MAPKs. Conversely, immunostimulatory agents, such as IFN-γ, suppress MKP-1 expression to promote MAPK activation. (B) At the posttranslational level, acetylation of Lys57 of the MKP-1 protein promotes its association with p38 MAPK, and phosphorylation of Ser359 and Ser364 in the C terminus of MKP-1 by ERK enhances its stability. ROS-dependent oxidation of the catalytic Cys258 of MKP-1 inactivates its phosphatase activity, whereas phosphorylation of Ser296 and Ser323 by sustained ERK activation leads to proteasomal degradation of MKP-1. KIM, kinase-interaction motif.
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