A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy
A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy
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结核分枝杆菌表面蛋白招募泛素来触发宿主异体吞噬
DOI：
10.1038/s41467-019-09955-8
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发表时间：
2019-04-29
影响因子：
16.6
通讯作者：
Liu, Cui Hua
中科院分区：
文献类型：
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作者：
Chai, Qiyao;Wang, Xudong;Liu, Cui Hua
泛素介导的异种吞噬是一种选择性自噬，在宿主防御结核分枝杆菌等胞内病原体的过程中起着重要作用。然而，宿主泛素靶向入侵微生物以触发异食的确切机制仍然不清楚。在这里，我们表明，泛素可以识别结核分枝杆菌表面蛋白Rv 1468 c，一个以前未确定的泛素结合蛋白含有真核生物一样的泛素相关（乌巴）结构域。UBA介导的泛素与Rv 1468 c的直接结合，而不是E3泛素连接酶介导的Rv 1468 c的泛素化，招募自噬受体p62将分枝杆菌递送到LC 3相关的自噬体中。Rv 1468 c-泛素相互作用的破坏减弱了巨噬细胞中Mtb的异种吞噬清除，并增加了炎症反应升高的小鼠中的细菌负荷。总之，我们的研究结果揭示了一个独特的机制，宿主xenophagy引发的直接结合的泛素的病原体表面蛋白，并表明外交战略所采取的结核分枝杆菌，以有利于其持续的细胞内感染，通过控制细胞内的细菌负荷和限制主机炎症反应。
Ubiquitin-mediated xenophagy, a type of selective autophagy, plays crucial roles in host defense against intracellular pathogens includingMycobacterium tuberculosis(Mtb). However, the exact mechanism by which host ubiquitin targets invaded microbes to trigger xenophagy remains obscure. Here we show that ubiquitin could recognize Mtb surface protein Rv1468c, a previously unidentified ubiquitin-binding protein containing a eukaryotic-like ubiquitin-associated (UBA) domain. The UBA-mediated direct binding of ubiquitin to, but not E3 ubiquitin ligases-mediated ubiquitination of, Rv1468c recruits autophagy receptor p62 to deliver mycobacteria into LC3-associated autophagosomes. Disruption of Rv1468c-ubiquitin interaction attenuates xenophagic clearance of Mtb in macrophages, and increases bacterial loads in mice with elevated inflammatory responses. Together, our findings reveal a unique mechanism of host xenophagy triggered by direct binding of ubiquitin to the pathogen surface protein, and indicate a diplomatic strategy adopted by Mtb to benefit its persistent intracellular infection through controlling intracellular bacterial loads and restricting host inflammatory responses.