The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways.
The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways.
复制标题
DOI：
10.1038/cdd.2017.17
复制
发表时间：
2017-07
影响因子：
12.4
通讯作者：
Strickson S
中科院分区：
文献类型：
--
作者：
Cohen P;Strickson S
受体蛋白MyD88是toll样受体和白细胞介素-1细胞因子家族受体传递信号所必需的。MyD88信号在几分钟内触发Lys63-linked和Met1-linked泛素（K63-Ub, M1-Ub）链的形成。由E3泛素连接酶TRAF6、Pellino1和Pellino2形成的K63-Ub链可激活TAK1， TAK1是激活丝裂原活化蛋白（MAP）激酶级联的主激酶，并启动典型i - κ b激酶（IKK）复合物的激活。M1-Ub链由线性泛素链组装复合物（LUBAC）形成，与IKK复合物的NEMO （NF-κB必需调节剂）组分结合，TAK1激活IKK所需，但不激活MAP激酶。TRAF6的一个独立于E3连接酶的重要作用是将LUBAC招募到MyD88信号复合体中，在那里它识别预先形成的K63- ub链，这些K63- ub链连接到这些复合体的蛋白质组分上，如IRAK1 （IL-1受体相关激酶），产生含有两种类型连锁的泛素链，称为K63/M1-Ub杂交体。K63/M1-Ub杂交体的形成是几种先天免疫信号通路的一个特征，它允许与K63- ub或M1-Ub链相互作用的蛋白质共同募集。K63/M1-Ub杂交体的两个可能作用是促进tak1依赖性IKK复合物的激活，并通过募集A20和A20结合的NF-κB1抑制剂（ABIN1）来防止这些激酶的过度激活。这些蛋白限制TAK1和IKK复合物的激活，可能是通过与它们竞争与K63/M1-Ub杂交体的结合。K63/M1-Ub杂合体的形成也可能调节这些链中泛素键的水解速率。ikk催化的一些底物磷酸化允许它们被E3连接酶SCFβTRCP识别，导致它们与lys48相关的泛素化和蛋白酶体降解。因此，先天免疫信号是由三种不同类型的泛素连锁的形成和破坏控制的。
The adaptor protein MyD88 is required for signal transmission by toll-like receptors and receptors of the interleukin-1 family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex. The M1-Ub chains, which are formed by the linear ubiquitin chain assembly complex (LUBAC), bind to the NEMO (NF-κB essential modulator) component of the IKK complex and are required for TAK1 to activate IKKs, but not MAP kinases. An essential E3 ligase-independent role of TRAF6 is to recruit LUBAC into the MyD88 signalling complex, where it recognises preformed K63-Ub chains attached to protein components of these complexes, such as IRAK1 (IL-1 receptor-associated kinase), producing ubiquitin chains containing both types of linkage, termed K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways, permits the co-recruitment of proteins that interact with either K63-Ub or M1-Ub chains. Two likely roles for K63/M1-Ub hybrids are to facilitate the TAK1-dependent activation of the IKK complex and to prevent the hyperactivation of these kinases by recruiting A20 and A20-binding inhibitor of NF-κB1 (ABIN1). These proteins restrict activation of the TAK1 and IKK complexes, probably by competing with them for binding to K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids may also regulate the rate at which the ubiquitin linkages in these chains are hydrolysed. The IKK-catalysed phosphorylation of some of its substrates permits their recognition by the E3 ligase SCFβTRCP, leading to their Lys48-linked ubiquitylation and proteasomal degradation. Innate immune signalling is therefore controlled by the formation and destruction of three different types of ubiquitin linkage.
登录
查看更多内容
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
3.5
作者：
Heyninck, K;Kreike, MM;Beyaert, R
通讯作者：
Beyaert, R
影响因子：
4.1
作者：
Goh, Eddy T. H.;Arthur, J. Simon C.;Cohen, Philip
通讯作者：
Cohen, Philip
DOI：
10.1073/pnas.1320440111
发表时间：
2014-06-10
影响因子：
11.1
作者：
Ben-Addi, Abduelhakem;Mambole-Dema, Agnes;Ley, Steven C.
通讯作者：
Ley, Steven C.
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
通讯作者：
Dikic, Ivan