Inturi Raviteja, Mun Kwangchol, Singethan Katrin, Schreiner Sabrina, Punga Tanel
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
J Virol. 2018 Jan 17;92(3). doi: 10.1128/JVI.01154-17. Print 2018 Feb 1.
Human adenoviruses (HAdVs) are common human pathogens encoding a highly abundant histone-like core protein, VII, which is involved in nuclear delivery and protection of viral DNA as well as in sequestering immune danger signals in infected cells. The molecular details of how protein VII acts as a multifunctional protein have remained to a large extent enigmatic. Here we report the identification of several cellular proteins interacting with the precursor pVII protein. We show that the cellular E3 ubiquitin ligase MKRN1 is a novel precursor pVII-interacting protein in HAdV-C5-infected cells. Surprisingly, the endogenous MKRN1 protein underwent proteasomal degradation during the late phase of HAdV-C5 infection in various human cell lines. MKRN1 protein degradation occurred independently of the HAdV E1B55K and E4orf6 proteins. We provide experimental evidence that the precursor pVII protein binding enhances MKRN1 self-ubiquitination, whereas the processed mature VII protein is deficient in this function. Based on these data, we propose that the pVII protein binding promotes MKRN1 self-ubiquitination, followed by proteasomal degradation of the MKRN1 protein, in HAdV-C5-infected cells. In addition, we show that measles virus and vesicular stomatitis virus infections reduce the MKRN1 protein accumulation in the recipient cells. Taken together, our results expand the functional repertoire of the HAdV-C5 precursor pVII protein in lytic virus infection and highlight MKRN1 as a potential common target during different virus infections. Human adenoviruses (HAdVs) are common pathogens causing a wide range of diseases. To achieve pathogenicity, HAdVs have to counteract a variety of host cell antiviral defense systems, which would otherwise hamper virus replication. In this study, we show that the HAdV-C5 histone-like core protein pVII binds to and promotes self-ubiquitination of a cellular E3 ubiquitin ligase named MKRN1. This mutual interaction between the pVII and MKRN1 proteins may prime MKRN1 for proteasomal degradation, because the MKRN1 protein is efficiently degraded during the late phase of HAdV-C5 infection. Since MKRN1 protein accumulation is also reduced in measles virus- and vesicular stomatitis virus-infected cells, our results signify the general strategy of viruses to target MKRN1.
人腺病毒（HAdVs）是常见的人类病原体，编码一种高度丰富的组蛋白样核心蛋白VII，该蛋白参与病毒DNA的核转运与保护，以及在受感染细胞中隔离免疫危险信号。蛋白VII如何作为一种多功能蛋白发挥作用的分子细节在很大程度上仍不清楚。在此，我们报告了几种与前体pVII蛋白相互作用的细胞蛋白的鉴定。我们表明，细胞E3泛素连接酶MKRN1是HAdV-C5感染细胞中一种新的前体pVII相互作用蛋白。令人惊讶的是，在多种人类细胞系中，内源性MKRN1蛋白在HAdV-C5感染后期经历蛋白酶体降解。MKRN1蛋白的降解独立于HAdV E1B55K和E4orf6蛋白。我们提供的实验证据表明，前体pVII蛋白结合增强了MKRN1的自身泛素化，而加工后的成熟VII蛋白在该功能上存在缺陷。基于这些数据，我们提出，在HAdV-C5感染的细胞中，pVII蛋白结合促进MKRN1的自身泛素化，随后MKRN1蛋白被蛋白酶体降解。此外，我们表明麻疹病毒和水疱性口炎病毒感染会减少受体细胞中MKRN1蛋白的积累。综上所述，我们的结果扩展了HAdV-C5前体pVII蛋白在溶细胞病毒感染中的功能谱，并突出了MKRN1作为不同病毒感染期间潜在共同靶点的地位。人腺病毒（HAdVs）是引起多种疾病的常见病原体。为了实现致病性，HAdVs必须对抗多种宿主细胞抗病毒防御系统，否则这些系统会阻碍病毒复制。在本研究中，我们表明HAdV-C5组蛋白样核心蛋白pVII与一种名为MKRN1的细胞E3泛素连接酶结合并促进其自身泛素化。pVII和MKRN1蛋白之间的这种相互作用可能使MKRN易于蛋白酶体降解，因为MKRN1蛋白在HAdV-C5感染后期被有效降解。由于在麻疹病毒和水疱性口炎病毒感染的细胞中MKRN1蛋白积累也减少，我们的结果表明病毒靶向MKRN1的一般策略。
