Menon Manoj B, Gaestel Matthias
Institute of Physiological Chemistry, Hannover Medical University, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Biochem J. 2016 Oct 1;473(19):2995-9. doi: 10.1042/BCJ20160672C.
The activation of p38(MAPK) by Toll-like receptor signalling is essential for the inflammatory response of innate immunity due to its role in post-transcriptional regulation of TNFα and cytokine biosynthesis. p38(MAPK) activation proceeds by the upstream MAP2Ks, MAPK kinase (MKK)3/6 as well as MKK4, which in turn are substrates for MAP3Ks, such as TGFβ-activated protein kinase-1 (TAK1). In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2-triggering activation of the classical ERKs, ERK1/2. In the recent issue of the Biochemical Journal, Pattison et al report their screening for TPL2 substrates in LPS-stimulated macrophages and the identification of MKK3/6. Using catalytic-dead TPL2 (Map3k8(D270A/D270A)) knockin macrophages, they demonstrated that activation of MKK3/6 by TPL2 significantly contributes to LPS-dependent TNFα biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IκB kinase, p105 NFκB and TPL2 to MKK3/6 and p38(MAPK) is established in macrophages. Taking into account that some isoforms of p38(MAPK) are necessary for maintaining functional steady-state levels of TPL2, a positive feedback loop in inflammation emerges.
Toll样受体信号传导对p38（丝裂原活化蛋白激酶）的激活对于天然免疫的炎症反应至关重要，因为它在肿瘤坏死因子α（TNFα）的转录后调控和细胞因子生物合成中发挥作用。p38（丝裂原活化蛋白激酶）的激活由上游的丝裂原活化蛋白激酶激酶（MAP2K）、丝裂原活化蛋白激酶激酶（MKK）3/6以及MKK4介导，而这些蛋白激酶又是丝裂原活化蛋白激酶激酶激酶（MAP3K）的底物，比如转化生长因子β激活蛋白激酶-1（TAK1）。相比之下，TPL2被描述为MKK1/贰触发经典细胞外信号调节激酶（ERK）1/2激活的唯一MAP3K。在最近一期的《生物化学杂志》中，帕蒂森等人报道了他们在脂多糖（LPS）刺激的巨噬细胞中对TPL2底物的筛选以及MKK3/6的鉴定。通过使用催化失活的TPL2（Map3k8（D270A/D270A））敲入巨噬细胞，他们证明TPL2对MKK3/6的激活显著促进了LPS依赖的TNFα生物合成，并且对TNF受体1信号传导也至关重要。因此，在巨噬细胞中建立了一条从TAK1经IκB激酶、p105核因子κB（NFκB）和TPL2到MKK3/6和p38（丝裂原活化蛋白激酶）的新信号通路。考虑到p38（丝裂原活化蛋白激酶）的一些亚型对于维持TPL2的功能稳态水平是必需的，炎症中的一个正反馈回路就出现了。
