Abstract
In infected cells rotavirus (RV) replicates in viroplasms, cytosolic structures that require a stabilized microtubule (MT) network for their assembly, maintenance of the structure and perinuclear localization. Therefore, we hypothesized that RV could interfere with the MT-breakdown that takes place in mitosis during cell division. Using synchronized RV-permissive cells, we show that RV infection arrests the cell cycle in S/G2 phase, thus favoring replication by improving viroplasms formation, viral protein translation, and viral assembly. The arrest in S/G2 phase is independent of the host or viral strain and relies on active RV replication. RV infection causes cyclin B1 down-regulation, consistent with blocking entry into mitosis. With the aid of chemical inhibitors, the cytoskeleton network was linked to specific signaling pathways of the RV-induced cell cycle arrest. We found that upon RV infection Eg5 kinesin was delocalized from the pericentriolar region to the viroplasms. We used a MA104-Fucci system to identify three RV proteins (NSP3, NSP5, and VP2) involved in cell cycle arrest in the S-phase. Our data indicate that there is a strong correlation between the cell cycle arrest and RV replication.
Highlights
Rotavirus (RV), a member of the Reoviridae family, is an icosahedral, non-enveloped, triplelayered particle responsible for severe diarrhea and dehydration in infants and young animals
Several reasons have been proposed to explain the link between the cell cycle arrest with RNA viruses, including i) increase in the efficiency of the viral replication and translation; ii) improvement in virus assembly and iii) a delay of apoptosis of the infected cells [66]
We present strong evidence indicating that RV infection arrests the host cell cycle in S/ G2 phase
Summary
Rotavirus (RV), a member of the Reoviridae family, is an icosahedral, non-enveloped, triplelayered particle responsible for severe diarrhea and dehydration in infants and young animals. The dynamics of the viroplasms involve their movement from the cell periphery towards the perinuclear region. Both coalescence and perinuclear distribution of the viroplasms depend on a stable MT-network [18]. The viral proteins NSP5, VP2, and NSP2 are directly involved in the formation of viroplasms and act as recruiters for the components of the viral replication intermediates [19,20,21,22]. NSP2 and VP2 have different tasks in the viroplasm dynamics: NSP2 associate to MTs permitting viroplasms coalescence, whereas VP2 has a role in viroplasms perinuclear distribution [18, 23]. The exact role of NSP5 in the RV replicative cycle remains yet to be elucidated [24, 25]
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