Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense
Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense
复制标题
DOI：
10.7554/elife.21465
复制
发表时间：
2017-03-28
期刊：
影响因子：
7.7
通讯作者：
Rudel, Thomas
中科院分区：
文献类型：
--
作者：
Fischer, Annette;Harrison, Kelly S.;Rudel, Thomas
专性细胞内沙眼衣原体在称为包涵体的膜结合液泡中复制，该液泡充当与宿主细胞的信号传导界面。在这里，我们发现衣原体去泛素化酶 (Cdu) 1 位于包涵膜中，并面向具有活性去泛素化酶结构域的胞质溶胶。该结构域的结构与哺乳动物去泛素酶高度相似，具有靠近底物结合口袋的独特α螺旋。我们将凋亡调节因子 Mcl-1 确定为与 Cdu1 相互作用的靶标，并通过衣原体包涵体的去泛素化来稳定。 Cdu1 编码基因中的衣原体转座子插入突变体表现出 Mcl-1 和包涵泛素化增加，以及 Mcl1 稳定性降低。此外，Cdu1 失活导致沙眼衣原体对 IFNγ 的敏感性增加，并损害小鼠的感染。因此，衣原体包涵体充当去泛素化活性的富集位点，发挥选择性稳定宿主蛋白和免受宿主防御的作用。
Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique a-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNy and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.