Innate immune signaling in Drosophila is regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing
Innate immune signaling in Drosophila is regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing
复制标题
DOI：
10.1074/jbc.m117.788158
复制
发表时间：
2017-05-26
影响因子：
4.8
通讯作者：
Silverman, Neal
中科院分区：
文献类型：
--
作者：
Chen, Li;Paquette, Nicholas;Silverman, Neal
先天免疫反应的协调调节在所有后生动物中是必要的。在果蝇中，Imd途径通过识别二氨基庚二酸（DAP）型肽聚糖和激活NF-κ B前体Relish检测革兰氏阴性细菌感染，这驱动了强大的抗菌肽基因表达。Imd是与哺乳动物RIP 1同源的受体近端衔接蛋白，其受蛋白水解切割和Lys-63-聚泛素化调节。然而，控制Imd翻译后修饰的精确事件和分子机制仍不清楚。在这里，我们证明，Imd是快速的赖氨酸-63-聚泛素化的赖氨酸残基137和153的顺序行动的两个E2酶，Ubc 5和Ubc 13-Uev 1a，在E3连接酶Diap 2。Lys-63-泛素化激活TGF β激活的激酶（Tak 1），其反馈磷酸化Imd，引发Lys-63链的去除和Lys-48聚泛素的添加。这种泛素编辑过程导致Imd的蛋白酶体降解，我们提出了恢复果蝇免疫反应稳态的功能。
Coordinated regulation of innate immune responses is necessary in all metazoans. In Drosophila the Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-kappa B precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear. Here, we demonstrate that Imd is rapidly Lys-63-polyubiquitinated at lysine residues 137 and 153 by the sequential action of two E2 enzymes, Ubc5 and Ubc13-Uev1a, in conjunction with the E3 ligase Diap2. Lys-63-ubiquitination activates the TGF beta-activated kinase (Tak1), which feeds back to phosphorylate Imd, triggering the removal of Lys-63 chains and the addition of Lys-48 polyubiquitin. This ubiquitin-editing process results in the proteasomal degradation of Imd, which we propose functions to restore homeostasis to the Drosophila immune response.