Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling.
Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling.
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DOI：
10.1084/jem.20071728
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发表时间：
2008-06-09
期刊：
影响因子：
--
通讯作者：
Lowenstein CJ
中科院分区：
文献类型：
--
作者：
Cao W;Bao C;Padalko E;Lowenstein CJ
丝裂原活化蛋白激酶（MAPK）通路在Toll样受体（TLR）信号转导中起着关键作用。MAPK磷酸酶-1（MKP-1）抑制MAPK通路并减少TLR信号传导，但MKP-1的调节尚未完全了解。我们现在表明，MKP-1是乙酰化的，乙酰化调节其与底物相互作用并使炎症信号失活的能力。我们发现LPS激活MKP-1的乙酰化。MKP-1在其底物结合结构域内的赖氨酸残基K57上被p300乙酰化。MKP-1的乙酰化增强其与p38的相互作用，从而增加其磷酸酶活性并中断MAPK信号传导。在野生型（WT）细胞中，抑制脱乙酰酶可增加MKP-1乙酰化并阻断MAPK信号传导;然而，脱乙酰酶抑制剂对缺乏MKP-1的细胞没有影响。此外，组蛋白去乙酰化酶抑制剂降低了LPS处理的WT小鼠的炎症和死亡率，但未能保护MKP-1敲除小鼠。我们的数据表明，乙酰化的MKP-1抑制先天免疫信号。该途径可能是治疗炎症性疾病的重要治疗靶点。
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.
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影响因子：
56.9
作者：
Ge, BX;Gram, H;Han, JH
通讯作者：
Han, JH
影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.1084/jem.20051753
发表时间：
2006-01-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
通讯作者：
Lang R
DOI：
10.1084/jem.20031237
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Doyle SE;O'Connell RM;Miranda GA;Vaidya SA;Chow EK;Liu PT;Suzuki S;Suzuki N;Modlin RL;Yeh WC;Lane TF;Cheng G
通讯作者：
Cheng G
影响因子：
30.8
作者：
Bereshchenko, OR;Gu, W;Dalla-Favera, R
通讯作者：
Dalla-Favera, R