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bioRxiv · 10.1101/328997

Inhibitor of sarco/endoplasmic reticulum calcium-ATPase impairs paramyxovirus replication

Kumar, N.·Barua, S.·Tripathi, B. N.·Khandelwal, N.·Riyesh, T.·Krishan, R. D.·Jangir, R. K.·Chander, Y.·Chaubey, K. K.·Singh, S. V.
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Abstract

Sarco/endoplasmic reticulum calcium-ATPase (SERCA) is a membrane bound cytosolic enzyme that is known to regulate the uptake of calcium into the sarco/endoplasmic reticulum. Herein, we demonstrate for the first time that SERCA can also regulate paramyxovirus [Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV)] replication. Treatment of Vero cells with SERCA specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced virus replication. Conversely, overexpression of SERCA rescued the inhibitory effect of Thapsigargin on virus replication. PPRV/NDV infection induced SERCA expression in Vero cells which could be blocked by Thapsigargin. With the help of time-of-addition and virus step-specific assays, it was observed that Thapsigargin specifically inhibits viral entry and subcellular localization of the viral proteins. Furthermore, NDV, but not PPRV acquired a significant resistance to Thapsigargin on long-term passage (P=70) in Vero cells. To the best of our knowledge, this is the first report describing virus supportive role of SERCA and a rare report suggesting that viruses may acquire resistance even in the presence of an inhibitor that targets a cellular factor. This study will contribute in understanding paramyxovirus replication and development of antiviral therapeutics using SERCA (host factor) as a candidate drug target.

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Kumar, N., Barua, S., Tripathi, B. N., Khandelwal, N., Riyesh, T., Krishan, R. D., Jangir, R. K., Chander, Y., Chaubey, K. K., Singh, S. V.. 2018-05-23. Inhibitor of sarco/endoplasmic reticulum calcium-ATPase impairs paramyxovirus replication. https://doi.org/10.1101/328997

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