Subversion of GBP-mediated host defense by E3 ligases acquired during Yersinia pestis evolution.
Subversion of GBP-mediated host defense by E3 ligases acquired during Yersinia pestis evolution.
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鼠疫耶尔森菌进化过程中获得的 E3 连接酶破坏 GBP 介导的宿主防御
DOI：
10.1038/s41467-022-32218-y
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发表时间：
2022-08-04
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
鼠疫在历史上曾造成过三次世界性的大流行，包括中世纪的黑死病。鼠疫耶尔森氏菌是鼠疫的病原体，在由肠致病性耶尔森氏菌进化而来的过程中，已经进化出一个强大的武器库来破坏宿主的免疫防御。假结核在此，我们发现Y.鼠疫杆菌YspE 1和YspE 2可以通过III型分泌注射体递送到宿主胞质溶胶中，在那里它们泛素化多种鸟苷酸结合蛋白（GBP）用于蛋白酶体降解。然而，Y.假结核病由于缺乏功能性YspE 1/2同源物而没有这种能力。YspE 1/2介导的GBP降解显著促进Y.鼠疫杆菌在巨噬细胞中，并强烈抑制炎性小体激活。相比之下，Gbpchr 3-/-、chr 5-/-巨噬细胞表现出与YspE 1/2无关的炎性小体激活大大降低，并伴有Y的复制增强。鼠疫因此，Gbpchr 3 −/−、chr 5 −/−小鼠更易感染Y。鼠疫我们证明了Y.鼠疫菌利用E3连接酶破坏GBP-mediated宿主防御，这似乎是由Y.瘟疫的进化鸟苷酸结合蛋白（GBP）识别含有空泡的病原体，导致细胞内小生境的裂解和炎性小体的诱导。在这里，Cao等人证明Y.鼠疫杆菌分泌两种功能冗余的E3连接酶YspE 1和YspE 2进入宿主细胞质，泛素化多个GBP，进行蛋白酶体降解，破坏宿主免疫防御。这种能力似乎是Y新获得的。鼠疫菌在进化过程中，因为其密切相关的祖先Y。假结核病不能这样做。
Plague has caused three worldwide pandemics in history, including the Black Death in medieval ages. Yersinia pestis, the etiological agent of plague, has evolved a powerful arsenal to disrupt host immune defenses during evolution from enteropathogenic Y. pseudotuberculosis. Here, we find that two functionally redundant E3 ligase of Y. pestis, YspE1 and YspE2, can be delivered via type III secretion injectisome into host cytosol where they ubiquitinate multiple guanylate-binding proteins (GBPs) for proteasomal degradation. However, Y. pseudotuberculosis has no such capability due to lacking functional YspE1/2 homologs. YspE1/2-mediated GBP degradations significantly promote the survival of Y. pestis in macrophages and strongly inhibit inflammasome activation. By contrast, Gbpchr3−/−, chr5−/− macrophages exhibit much lowered inflammasome activation independent of YspE1/2, accompanied with an enhanced replication of Y. pestis. Accordingly, Gbpchr3−/−, chr5−/− mice are more susceptible to Y. pestis. We demonstrate that Y. pestis utilizes E3 ligases to subvert GBP-mediated host defense, which appears to be newly acquired by Y. pestis during evolution. Guanylate-binding proteins (GBPs) recognize pathogen containing vacuoles, leading to lysis of this intracellular niche and induction of inflammasomes. Here, Cao et al. show that Y. pestis, the causative agent of plague, secret two functionally redundant E3 ligase, YspE1 and YspE2, into the host’s cytosol to ubiquitinate multiple GBPs for proteasomal degradation to subvert host immune defense. This capability appears to be newly acquired by Y. pestis during evolution, since its closely related progenitor Y. pseudotuberculosis is unable to do so.
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