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Tuesday, February 06, 2018 9:58:30 AM
Published: January 16, 2018
Abstract
Cell surface receptors for phosphatidylserine contribute to the entry of Ebola virus (EBOV) particles, indicating that the presence of phosphatidylserine in the envelope of EBOV is important for the internalization of EBOV particles. Phosphatidylserine is typically distributed in the inner layer of the plasma membrane in normal cells. Progeny virions bud from the plasma membrane of infected cells, suggesting that phosphatidylserine is likely flipped to the outer leaflet of the plasma membrane in infected cells for EBOV virions to acquire it. Currently, the intracellular dynamics of phosphatidylserine during EBOV infection are poorly understood. Here, we explored the role of XK-related protein (Xkr) 8, which is a scramblase responsible for exposure of phosphatidylserine in the plasma membrane of apoptotic cells, to understand its significance in phosphatidylserine-dependent entry of EBOV. We found that Xkr8 and transiently expressed EBOV glycoprotein GP often co-localized in intracellular vesicles and the plasma membrane. We also found that co-expression of GP and viral major matrix protein VP40 promoted incorporation of Xkr8 into ebolavirus-like particles (VLPs) and exposure of phosphatidylserine on their surface, although only a limited amount of phosphatidylserine was exposed on the surface of the cells expressing GP and/or VP40. Downregulating Xkr8 or blocking caspase-mediated Xkr8 activation did not affect VLP production, but they reduced the amount of phosphatidylserine on the VLPs and their uptake in recipient cells. Taken together, our findings indicate that Xkr8 is trafficked to budding sites via GP-containing vesicles, is incorporated into VLPs, and then promote the entry of the released EBOV to cells in a phosphatidylserine-dependent manner.
Author summary
Although Ebola virus causes severe hemorrhagic fever with a high mortality rate, there are no approved therapeutics. The viral entry process is one of the targets for antiviral development. Previous studies suggest that binding of phosphatidylserine, a component of the viral envelop, to the receptors promotes the entry of Ebola virus. Ebola virus is released from the surface membrane of infected cells. However, phosphatidylserine normally distributes in the inner layer of the cell surface membrane, suggesting that phosphatidylserine is likely flipped to the outer leaflet of the membrane in infected cells for Ebola virus to acquire it. Because the mechanism by which phosphatidylserine changes its orientation in Ebola virus-infected cells is poorly understood, we studied and identified a cellular enzyme, XK-related protein 8 (Xkr8), as a responsible factor involved in this process. We demonstrated that the Ebola virus glycoprotein promoted the incorporation of Xkr8 in viral particles, which flips phosphatidylserine on their surface, enhancing their entry to cells. Our findings provide new insights into the mechanism of Ebola virus infection, which may be exploited for the development of therapeutics against Ebola virus infection.
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006848
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