SUMO and ubiquitin modifications in Nipah virus matrix trafficking and function

描述(申请人提供)：Nipah(Niv)和Hendra(HEV)病毒是副粘病毒科家族中最致命的人类病原体，包括具有全球生物医学重要性的人和动物病原体。新城疫病毒和戊型肝炎病毒是人畜共患病病毒，可从果蝠体内的天然宿主直接传播给人类或中间放大宿主。新城疫和戊型肝炎病毒感染会导致呼吸道和脑部疾病，新城疫病毒在人类中的死亡率可超过70%。因此，新城疫病毒和戊型肝炎病毒是唯一被归类为BSL4病原体的副粘病毒，因为它们具有极强的致病性，而且缺乏获得许可的疫苗或有效的治疗方法。副粘病毒是在细胞质中复制的负义RNA病毒。它们的基质结构蛋白在质膜上组织病毒粒子组装，并介导病毒从细胞表面萌发。奇怪的是，已经观察到几种副粘病毒的基质蛋白进出细胞核，尽管进入细胞核的副粘病毒M蛋白的功能相关性尚不清楚。我们还发现，Niv-M穿梭于细胞质和核间。然而，我们的研究发现，在泛素-蛋白酶体系统的调控下，NIV-M的适当核质转运对于其功能定位到质膜以及随后介导病毒萌发的能力至关重要。进一步的研究揭示了大量NIV-M相互作用的伙伴，它们将NIV-M置于当代科学感兴趣的多种细胞生物学过程的结合点，包括相扑和泛素-蛋白酶体系统之间在调节亚核运输中的CROS调节，以及PML小体的功能，即参与细胞抗病毒防御的核结构。本申请的目的是确定相扑和泛素修饰在尼帕病毒基质运输和功能中的作用。了解新城疫病毒M的基本细胞生物学将不仅有助于阐明导致异常高毒力的特性 但也可能揭示宿主-病原体之间的相互作用，这对病毒的一般致病机理具有更广泛的影响。为了了解Niv-M复杂的细胞内停留的生物学意义，我们提出了以下三个具体目标：(1)识别和表征Niv-M的翻译后修饰，重点是SUMO-和泛素-蛋白酶体途径；(2)确定基质翻译后修饰的功能作用 病毒致病机制。

DESCRIPTION (provided by applicant): Nipah (NiV) and Hendra (HeV) viruses are the deadliest human pathogens within the Paramyxoviridae family, which include human and animal pathogens of global biomedical importance. NiV and HeV are zoonotic viruses that can be transmitted directly to humans or intermediate amplifying hosts from their natural reservoirs in fruit bats. NiV and HeV infections cause respiratory and encephalitic illnesses, and NiV's mortality rate in humans can exceed 70 percent. Thus, NiV and HeV are the only paramyxoviruses classified BSL4 pathogens due to their extreme pathogenicity and lack of licensed vaccines or effective therapeutics. Paramyxoviruses are negative-sense RNA viruses that replicate in the cytoplasm. Their matrix structural protein organizes virion assembly at the plasma membrane and mediates viral budding from the cell surface. Curiously, the matrix protein of several paramyxoviruses has been observed to traffic in and out of the nucleus, although the functional relevance of paramyxovirus M proteins entering the nucleus has been unclear. We also found that NiV-M shuttles between the cytoplasmic and the nuclear compartments. However, our investigations established that proper nuclear-cytoplasmic trafficking of NiV-M, regulated by the ubiquitin-proteasome system, is critical for its functional localization to the plasma membrane, and its subsequent ability to mediate viral budding. Further study revealed a trove of NiV-M-interacting partners that places NiV-M at the nexus of multiple cell biological processes that are of contemporary scientific interest, including the cros regulation between the SUMO and ubiquitin-proteasome system in modulating subnuclear trafficking, and the function of PML bodies, nuclear structures involved in cellular antiviral defense. The goal of this application is to determine the role of SUMO and ubiquitin modifications in Nipah virus matrix trafficking and function. Understanding the basic cell biology of NiV-M will not only shed light on the properties that contribute to the unusually high virulence of this virus, but might also reveal host-pathogen interactions that have broader implications for viral pathogenesis in general. To understand the biological implications of NiV-M's complex intracellular sojourn, we propose the following three specific aims: (1) Identify and characterize post-translational modifications of NiV-M, focusing on the SUMO- and ubiquitin-proteasome pathway, and (2) define the functional roles for matrix post-translational modification in relation to viral pathogenesis.