Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China.
Nat Commun. 2019 Apr 29;10(1):1973. doi: 10.1038/s41467-019-09955-8.
Ubiquitin-mediated xenophagy, a type of selective autophagy, plays crucial roles in host defense against intracellular pathogens including Mycobacterium 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.
泛素介导的异噬作用是一种选择性自噬，在宿主防御包括结核分枝杆菌（Mtb）在内的细胞内病原体中发挥着关键作用。然而，宿主泛素靶向入侵微生物以触发异噬的确切机制仍不清楚。在这里，我们表明泛素可以识别 Mtb 表面蛋白 Rv1468c，这是一种以前未被识别的泛素结合蛋白，含有一个真核样泛素相关（UBA）结构域。UBA 介导的泛素对 Rv1468c 的直接结合，而不是 E3 泛素连接酶介导的 Rv1468c 泛素化，招募自噬受体 p62 将分枝杆菌递送至 LC3 相关自噬体中。破坏 Rv1468c-泛素相互作用会减弱巨噬细胞中对 Mtb 的异噬清除，并增加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种由泛素与病原体表面蛋白直接结合触发的宿主异噬作用的独特机制，并表明结核分枝杆菌通过控制细胞内细菌负荷和限制宿主炎症反应，采用了一种外交策略来促进其持续的细胞内感染。
