Porcine circovirus type 2 (PCV2) infection causes porcine circovirus associated diseases (PCVAD) worldwide. Identification of host factors that interact with viral proteins is a fundamental step to understand the pathogenesis of PCV2. Our previous study reported that ORF5, a newly identified PCV2 viral protein supports PCV2 replication and interacts with multiple host factors. Here, we showed that a host factor YWHAB is an ORF5-interacting protein and plays essential roles during PCV2 infection. By using protein-protein interaction assays, we confirmed that YWHAB directly interacts with PCV2-ORF5 protein. We further showed that YWHAB expression was potently induced upon ORF5 overexpression and PCV2 infection. Remarkably, we found that the YWHAB strongly inhibited PCV2 replication, suggesting its role in defending PCV2 infection. By using the ectopic overexpression and gene knockdown approaches, we revealed that YWHAB inhibits PCV2-induced endoplasmic reticulum stress (ERS), autophagy, reactive oxygen species (ROS) production and apoptosis, suggesting its vital role in alleviating PCV2-induced cellular damage. Together, this study demonstrated that an ORF5-interacting host factor YWHAB affects PCV2 infection and PCV2-induced cellular response, which expands the current understanding of YWHAB biological function and might serves as a new therapeutic target to manage PCV2 infection-associated diseases.

猪圆环病毒2型（PCV2）感染导致世界范围内的猪圆环病毒相关疾病（PCVAD）。鉴定与病毒蛋白相互作用的宿主因子是了解PCV2发病机理的基本步骤。我们先前的研究报告说，ORF5是一种新鉴定的PCV2病毒蛋白，可支持PCV2复制并与多种宿主因子相互作用。在这里，我们表明宿主因子YWHAB是一种ORF5相互作用蛋白，在PCV2感染过程中起着至关重要的作用。通过使用蛋白质-蛋白质相互作用测定，我们证实了YWHAB与PCV2-ORF5蛋白质直接相互作用。我们进一步表明，在ORF5过表达和PCV2感染后，YWHAB表达被有效诱导。值得注意的是，我们发现YWHAB强烈抑制PCV2复制，表明其在防御PCV2感染中的作用。通过使用异位过表达和基因敲低方法，我们发现YWHAB抑制PCV2诱导的内质网应激（ERS），自噬，活性氧（ROS）产生和凋亡，提示其在减轻PCV2诱导的细胞损伤中的重要作用。总之，这项研究表明，与ORF5相互作用的宿主因子YWHAB影响PCV2感染和PCV2诱导的细胞反应，从而扩大了对YWHAB生物学功能的当前了解，并可能成为管理PCV2感染相关疾病的新治疗靶标。