Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
PLoS Pathog. 2019 Aug 5;15(8):e1007962. doi: 10.1371/journal.ppat.1007962. eCollection 2019 Aug.
Enteroviruses, members of the family of picornaviruses, are the most common viral infectious agents in humans causing a broad spectrum of diseases ranging from mild respiratory illnesses to life-threatening infections. To efficiently replicate within the host cell, enteroviruses hijack several host factors, such as ACBD3. ACBD3 facilitates replication of various enterovirus species, however, structural determinants of ACBD3 recruitment to the viral replication sites are poorly understood. Here, we present a structural characterization of the interaction between ACBD3 and the non-structural 3A proteins of four representative enteroviruses (poliovirus, enterovirus A71, enterovirus D68, and rhinovirus B14). In addition, we describe the details of the 3A-3A interaction causing the assembly of the ACBD3-3A heterotetramers and the interaction between the ACBD3-3A complex and the lipid bilayer. Using structure-guided identification of the point mutations disrupting these interactions, we demonstrate their roles in the intracellular localization of these proteins, recruitment of downstream effectors of ACBD3, and facilitation of enterovirus replication. These structures uncovered a striking convergence in the mechanisms of how enteroviruses and kobuviruses, members of a distinct group of picornaviruses that also rely on ACBD3, recruit ACBD3 and its downstream effectors to the sites of viral replication.
肠道病毒是小 RNA 病毒科的成员，是人类最常见的病毒病原体，可引起广泛的疾病，从轻微的呼吸道疾病到危及生命的感染。为了在宿主细胞内高效复制，肠道病毒劫持了几种宿主因子，如 ACBD3。ACBD3 促进了多种肠道病毒的复制，然而，ACBD3 招募到病毒复制部位的结构决定因素还了解甚少。在这里，我们对 ACBD3 与四种代表性肠道病毒（脊髓灰质炎病毒、肠道病毒 A71、肠道病毒 D68 和鼻病毒 B14）的非结构 3A 蛋白之间的相互作用进行了结构表征。此外，我们还描述了 3A-3A 相互作用导致 ACBD3-3A 异四聚体组装的细节，以及 ACBD3-3A 复合物与脂质双层之间的相互作用。通过对破坏这些相互作用的点突变进行结构导向鉴定，我们证明了它们在这些蛋白质的细胞内定位、ACBD3 下游效应物的募集以及肠道病毒复制中的促进作用。这些结构揭示了肠道病毒和柯萨奇病毒（小 RNA 病毒科的一个不同组群的成员，也依赖于 ACBD3）如何招募 ACBD3 和其下游效应物到病毒复制部位的机制惊人地趋同。
