Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages
Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages
复制标题
Stk38蛋白激酶通过促进巨噬细胞中MEKK2泛素化优先抑制TLR9激活的炎症反应
DOI：
10.1038/ncomms8167
复制
发表时间：
2015-05-01
影响因子：
16.6
通讯作者：
An, Huazhang
中科院分区：
文献类型：
--
作者：
Wen, Mingyue;Ma, Xianwei;An, Huazhang
NDR/LATS激酶家族是从酵母到人类高度保守的。目前还不清楚这个家族的成员是否在先天免疫反应中起作用。在这里，我们证明了Stk 38负调节TLR 9介导的免疫反应在巨噬细胞。Stk 38与泛素E3连接酶Smurf 1组成型结合，并促进Smurf 1介导的MEKK 2泛素化和降解。MEKK 2是CpG诱导的ERK 1/2活化、TNF-α和IL-6产生所必需的，但不是LPS诱导的TNF-α和IL-6产生所必需的。因此，Stk 38缺陷增加CpG诱导的ERK 1/2活化、TNF-α和IL-6产生，而不显著影响LPS诱导的TNF-α和IL-6产生。Stk 38缺陷小鼠产生更多的TNF-α和IL-6，并显示出比对照野生型小鼠增加的致死率。大肠杆菌感染Stk 38缺陷型小鼠也比对照小鼠更易受CLP诱导的脓毒症的影响。因此，Stk 38在限制炎性细胞因子产生方面是重要的，并且可能通过负调节TLR 9信号传导而在感染期间保护宿主免受炎性损伤是必需的。
NDR/LATS kinase family is highly conserved from yeast to human. It remains unknown whether the members of this family function in innate immune responses. Here we demonstrate that Stk38 negatively regulates TLR9-mediated immune responses in macrophages. Stk38 constitutively associates with ubiquitin E3 ligase Smurf1, and facilitates Smurf1-mediated MEKK2 ubiquitination and degradation. MEKK2 is required for CpG-induced ERK1/2 activation, TNF-α and IL-6 production but not required for LPS-induced TNF-α and IL-6 production. Accordingly, Stk38 deficiency increases CpG-induced ERK1/2 activation, TNF-α and IL-6 production without significantly affecting LPS-induced TNF-α and IL-6 production. Stk38-deficient mice produce more TNF-α and IL-6, and display increased lethality than control wild-type mice uponE. coliinfection. Stk38-deficient mice are also more susceptible to CLP-induced sepsis than control mice. Thus, Stk38 is important in limiting inflammatory cytokine production and necessary for protecting host from inflammatory injury during infection, possibly by negatively regulating TLR9 signalling.