A protein-protein interaction map reveals that the Coxiella burnetii effector CirB inhibits host proteasome activity.
A protein-protein interaction map reveals that the Coxiella burnetii effector CirB inhibits host proteasome activity.
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蛋白质-蛋白质相互作用图谱揭示贝氏柯克斯体效应子CirB抑制宿主蛋白酶体活性。
DOI：
10.1371/journal.ppat.1010660
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发表时间：
2022-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
贝氏柯克斯体是人畜共患病Q热的病原体，其特征在于其在类似于溶酶体网络的酸性空泡中复制的能力。C. Burnetii是Dot/Icm系统，其将超过150种效应蛋白转移到宿主细胞中。这些效应子的功能是构建允许细菌复制的溶酶体样区室，但大多数这些效应子的功能仍然难以捉摸。在这项研究中，我们使用亲和标签纯化质谱（AP-MS）的方法来产生一个C。burnetii-人蛋白质-蛋白质相互作用（PPI）图谱涉及53个C。贝氏体效应子和3480种宿主蛋白质。PPI图显示C.贝氏菌效应子CBU 0425（命名为CirB）与20 S核心蛋白酶体的大多数亚基相互作用。我们发现，异位表达的CirB抑制蛋白酶体的水解活性。此外，CirB在C. Burnetii引起宿主细胞中蛋白酶体活性的显著抑制，而敲低CirB表达减轻了这种抑制作用。此外，我们发现CirB的一个区域，跨越残基91-120结合蛋白酶体亚基PSMB 5（β 5）。最后，PSMB 5敲低促进C. Burnettii毒力，强调蛋白酶体活性调节过程中的C。贝氏体感染作为Q热的病原体，C. Burnetii通过其Dot/Icm分泌系统将效应蛋白转移到宿主细胞质中以构建复制泡来定殖宿主细胞。效应器的功能在很大程度上仍然未知。在这里，我们进行了大规模的AP-MS筛选，以分析C。Burnetii效应子和人蛋白质。这些分析发现，CirB作为宿主蛋白酶体活性的抑制剂，揭示了蛋白酶体活性对于C.伯内特氏菌我们的研究结果为进一步探讨C.贝氏疟原虫效应子在其毒力方面的作用，以及用于鉴定用于开发针对贝氏疟原虫的新型治疗性治疗的新型潜在药物靶点。贝氏体感染
Coxiella burnetii is the etiological agent of the zoonotic disease Q fever, which is featured by its ability to replicate in acid vacuoles resembling the lysosomal network. One key virulence determinant of C. burnetii is the Dot/Icm system that transfers more than 150 effector proteins into host cells. These effectors function to construct the lysosome-like compartment permissive for bacterial replication, but the functions of most of these effectors remain elusive. In this study, we used an affinity tag purification mass spectrometry (AP-MS) approach to generate a C. burnetii-human protein-protein interaction (PPI) map involving 53 C. burnetii effectors and 3480 host proteins. This PPI map revealed that the C. burnetii effector CBU0425 (designated CirB) interacts with most subunits of the 20S core proteasome. We found that ectopically expressed CirB inhibits hydrolytic activity of the proteasome. In addition, overexpression of CirB in C. burnetii caused dramatic inhibition of proteasome activity in host cells, while knocking down CirB expression alleviated such inhibitory effects. Moreover, we showed that a region of CirB that spans residues 91–120 binds to the proteasome subunit PSMB5 (beta 5). Finally, PSMB5 knockdown promotes C. burnetii virulence, highlighting the importance of proteasome activity modulation during the course of C. burnetii infection. As the causative agent of Q fever, C. burnetii colonizes host cells by transferring effector proteins into the host cytoplasm through its Dot/Icm secretion system to construct a replicative vacuole. The function of effectors remains largely unknown. Here, we performed a large-scale AP-MS screen to analyze the interactions among C. burnetii effectors and human proteins. These analyses found that CirB functions as an inhibitor of host proteasome activity, revealing that proteasome activity is important for intracellular survival of C. burnetii. Our data have laid the foundation for future exploring the molecular mechanisms underlying the roles of C. burnetii effectors in its virulence and for the identification of novel potential drug targets for the development of novel therapeutic treatment for C. burnetii infection.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
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