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bioRxiv · 10.1101/619932

Rotavirus NSP1 localizes in the nucleus to disrupt PML nuclear bodies during infection

Murphy, S. K.·Arnold, M. M.
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Abstract

The rotavirus nonstructural protein 1 (NSP1) antagonizes interferon (IFN) induction in infected host cells. The primary function of NSP1 is thought to be degradation of interferon regulatory factors (IRFs) and beta-transducin repeat-containing protein ({beta}-TrCP) in the cytoplasm to inhibit IFN induction. Here, we report that NSP1 localizes to the cytoplasm and nucleus and disrupts promyelocytic (PML) nuclear bodies (NB) in the nucleus during infection. Nuclear localization of NSP1 did not require an intact C terminus, suggesting NSP1 has a novel function in the nucleus independent of degradation of IRFs or {beta}-TrCP. NSP1 expression either led to a reduction in PML NB number or a change in PML NB morphology from sphere-shaped foci to oblong-shaped structures, depending on the virus strain. Additionally, infection was not affected when cells lack PML NB, suggesting that rotavirus does not require PML for replication in highly permissive cell types. PML was not essential for nuclear localization of NSP1, but PML was required for NSP1 nuclear focus formation. PML NBs play an important role in many cellular functions that include IFN induction and host stress responses. This is the first report that rotavirus, a cytoplasmically replicating virus, encodes a viral protein that localizes to the nucleus during infection, and may suggest a new function of NSP1 in the nucleus.\n\nIMPORTANCERotavirus causes severe gastroenteritis in young children and leads to over 200,000 deaths per year. Rotavirus is a cytoplasmically replicating virus, and must find ways to avoid or actively inhibit host antiviral responses to efficiently replicate. The nonstructural protein NSP1 is known to inhibit IFN induction by promoting degradation of host proteins in the cytoplasm of infected cells. Here, we demonstrate that NSP1 also localizes to the nucleus of infected cells, specifically to PML NB. NSP1 causes a disruption of PML NB, which may serve as an additional mechanism of IFN inhibition or interfere with other nuclear processes to promote viral replication. A detailed exploration of the manipulation of nuclear processes in cells infected with cytoplasmically replicating viruses will lead to new insights into viral evasion of host responses.

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Murphy, S. K., Arnold, M. M.. 2019-04-26. Rotavirus NSP1 localizes in the nucleus to disrupt PML nuclear bodies during infection. https://doi.org/10.1101/619932

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