Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system
Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system
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DOI：
10.1042/bj20111415
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发表时间：
2012-01-01
影响因子：
4.1
通讯作者：
Cohen, Philip
中科院分区：
文献类型：
--
作者：
Goh, Eddy T. H.;Arthur, J. Simon C.;Cohen, Philip
E3泛素连接酶Pellino 1可以通过可逆的磷酸化机制在非活性和活性形式之间相互转化。在体外，磷酸化和活化可由IRAK [IL（白细胞介素）-1-受体相关激酶] IRAK 1和IRAK 4或IKK {I κ B [NF-κ B（核因子κ B）抑制剂]激酶}相关激酶[IKK β和TBK 1（TANK {TRAF [TNF（肿瘤坏死因子）-受体相关因子]-相关NF-κ B激活剂}-结合激酶1）]催化。在本研究中，我们确定IRAK I是介导MEFs（小鼠胚胎成纤维细胞）或HEK（人胚肾）-293细胞中IL-1刺激的Pellino 1活化的主要蛋白激酶，而IKK相关激酶在TNF α刺激的MEFs中活化Pellino 1。IKK相关激酶也是响应TLR（Toll样受体）配体激活Pellino 1的主要蛋白激酶，TLR（Toll样受体）配体通过衔接子MyD 88（髓样分化初级应答基因88）和/或TRIF [含有TIR（Toll/IL-1受体）结构域的衔接子蛋白诱导干扰素β]发出信号。目前的研究表明，令人惊讶的是，通过MyD 88发出信号的配体并不总是采用相同的蛋白激酶来激活Pellino 1。我们的研究结果还证实，无论是IRAK 1的催化活性还是Pellino 1的激活，对于由MEFs中的IL-1或TNF α或巨噬细胞中的TLR配体触发的NF-κ B和MAPK（促分裂原活化蛋白激酶）的初始瞬时激活都不是必需的。Pellino 1的激活提供了细胞中IRAK 1催化活性的第一个直接读数。
The E3 ubiquitin ligase Pellino 1 can be interconverted between inactive and active forms by a reversible phosphorylation mechanism. In vitro, phosphorylation and activation can be catalysed by either the IRAKs [IL (interleukin)-1-receptor-associated kinases] IRAK1 and IRAK4, or the IKK {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase}-related kinases [IKK epsilon and TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-kappa B activator}-binding kinase 1)]. In the present study we establish that IRAK I is the major protein kinase that mediates the IL-1-stimulated activation of Pellino 1 in MEFs (mouse embryonic fibroblasts) or HEK (human embryonic kidney)-293 cells, whereas the IKK-related kinases activate Pellino 1 in TNF alpha-stimulated MEFs. The IKK-related kinases are also the major protein kinases that activate Pellino 1 in response to TLR (Toll-like receptor) ligands that signal via the adaptors MyD88 (myeloid differentiation primary response gene 88) and/or TRIF [TIR (Toll/IL-1 receptor) domain-containing adaptor protein inducing interferon beta]. The present studies demonstrate that, surprisingly, the ligands that signal via MyD88 do not always employ the same protein kinase to activate Pellino 1. Our results also establish that neither the catalytic activity of IRAK1 nor the activation of Pellino 1 is required for the initial transient activation of NF-kappa B and MAPKs (mitogen-activated protein kinases) that is triggered by IL-1 or TNF alpha in MEFs, or by TLR ligands in macrophages. The activation of Pellino 1 provides the first direct readout for IRAK1 catalytic activity in cells.