Phosphoribosylation of Ubiquitin Promotes Serine Ubiquitination and Impairs Conventional Ubiquitination
Phosphoribosylation of Ubiquitin Promotes Serine Ubiquitination and Impairs Conventional Ubiquitination
复制标题
DOI：
10.1016/j.cell.2016.11.019
复制
发表时间：
2016-12-01
期刊：
影响因子：
64.5
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Bhogaraju, Sagar;Kalayil, Sissy;Dikic, Ivan
传统的泛素化涉及泛素C末端和底物蛋白中的伯胺之间的酰胺键的ATP依赖性形成。最近，SdeA，致病性嗜肺军团菌的效应蛋白，被证明介导NAD依赖和ATP非依赖的泛素转移到宿主蛋白。在这里，我们确定了一个磷酸二酯酶结构域SdeA，有效地催化磷酸核糖基化的泛素上的特定精氨酸通过ADP-核糖-泛素中间体。SdeA还通过磷酸二酯键将磷酸核糖基化泛素缀合至蛋白质底物的丝氨酸残基来催化化学和结构上不同类型的底物泛素化。此外，泛素的磷酸核糖基化阻止了常规泛素化级联的E1和E2酶的活化，从而损害了许多细胞过程，包括线粒体自噬、TNF信号传导和蛋白酶体降解。我们认为泛素的磷酸核糖基化可以有效地调节哺乳动物细胞中的泛素功能。
Conventional ubiquitination involves the ATP-dependent formation of amide bonds between the ubiquitin C terminus and primary amines in substrate proteins. Recently, SdeA, an effector protein of pathogenic Legionella pneumophila, was shown to mediate NAD-dependent and ATP-independent ubiquitin transfer to host proteins. Here, we identify a phosphodiesterase domain in SdeA that efficiently catalyzes phosphoribosylation of ubiquitin on a specific arginine via an ADP-ribose-ubiquitin intermediate. SdeA also catalyzes a chemically and structurally distinct type of substrate ubiquitination by conjugating phosphoribosylated ubiquitin to serine residues of protein substrates via a phosphodiester bond. Furthermore, phosphoribosylation of ubiquitin prevents activation of E1 and E2 enzymes of the conventional ubiquitination cascade, thereby impairing numerous cellular processes including mitophagy, TNF signaling, and proteasomal degradation. We propose that phosphoribosylation of ubiquitin potently modulates ubiquitin functions in mammalian cells.