Chi Hongbo, Flavell Richard A
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Sci Signal. 2008 Oct 14;1(41):pe44. doi: 10.1126/scisignal.141pe44.
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.
由Toll样受体（TLRs）介导的天然免疫反应，这是一类模式识别受体，在抵御微生物病原体中起着关键作用。然而，过度的TLR介导的反应会导致败血症、自身免疫和慢性炎症。为了防止TLRs的有害激活，细胞进化出了多种抑制天然免疫反应的机制。TLRs的刺激会诱导编码丝裂原活化蛋白激酶（MAPK）磷酸酶-1（MKP-1）的基因表达，MKP-1是一种定位于细胞核的双特异性磷酸酶，优先使p38 MAPK和c-Jun N端激酶（JNK）去磷酸化，从而导致TLR触发的促炎细胞因子产生减弱。MKP-1通过多种机制进行翻译后修饰，包括磷酸化。现在一项研究表明，TLRs刺激后，MKP-1在一个关键赖氨酸残基上也会发生乙酰化。MKP-1的乙酰化促进了MKP-1与其底物p38 MAPK的相互作用，这导致p38 MAPK去磷酸化并抑制天然免疫。
