The nucleolar interface of RNA viruses

Abstract

SummaryIn recent years, understanding of the nucleolus has undergone a renaissance. Once considered primarily as the sites of ribosome biogenesis, nucleoli are now understood to be highly dynamic, multifunctional structures that participate in a plethora of cellular functions including regulation of the cell cycle, signal recognition particle assembly, apoptosis and stress responses. Although the molecular/mechanistic details of many of these functions remain only partially resolved, it is becoming increasingly apparent that nucleoli are also common targets of almost all types of viruses, potentially allowing viruses to manipulate cellular responses and the intracellular environment to facilitate replication and propagation. Importantly, a number of recent studies have moved beyond early descriptive observations to identify key roles for nucleolar interactions in the viral life cycle and pathogenesis. While it is perhaps unsurprising that many viruses that replicate within the nucleus also form interactions with nucleoli, the roles of nucleoli in the biology of cytoplasmic viruses is less intuitive. Nevertheless, a number of positivestranded RNA viruses that replicate exclusively in the cytoplasm are known to express proteins that enter the nucleus and target nucleoli, and recent data have indicated similar processes in several cytoplasmic negative-sense RNA viruses. Here, we review this emerging aspect of the virus-host interface with a focus on examples where virusnucleolus interactions have been linked to specific functional outcomes/mechanistic processes in infection and on the nucleolar interfaces formed by viruses that replicate exclusively in the cytoplasm.

Strand-Specific Dual RNA Sequencing of Bronchial Epithelial Cells Infected with Influenza A/H3N2 Viruses Reveals Splicing of Gene Segment 6 and Novel Host-Virus Interactions

“…The nucleolus is the subnuclear compartment for ribosome biogenesis and cellular location of SNORAs and SNORDs. It is also involved in the regulation of cellular processes such as cell cycle, apoptosis, and RNA processing (73). Thus, it is likely that the nucleolus acts as a platform for the virus to manipulate processes such as cell growth and stress response, whose inhibition would encourage viral pathogenesis (73).…”

Nonstructural Protein NSs of Schmallenberg Virus Is Targeted to the Nucleolus and Induces Nucleolar Disorganization

“…The nucleolus is highly dynamic and plays fundamental roles in cellular stress responses, innate immune responses, or cell cycle regulation (reviewed in reference 23). Given the variety of key functions ensured by the nucleolus, many viruses that replicate in the nucleus (DNA viruses, retroviruses, and some negative-stranded RNA viruses) have usurped the nucleolus to favor their own replication (24–27). There are now many examples of viral proteins targeting the nucleolus, but the molecular function behind this localization is often uncertain or unresolved.…”

“…These results raise the question about the link between nucleolar localization of NSs and transcription inhibition. Among the multiple strategies evolved by viruses to interfere with the host transcription machinery (29), nucleolar targeting is a common mechanism shared by several picornaviruses (24, 30). Indeed, the 3C pro protease of poliovirus blocks RNA Pol I synthesis through modification and inactivation of factors essential for rRNA transcription, upstream binding factor (UBF) and selectivity factor 1 (SL1) possibly involving its proteolytic activity (31).…”

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

“…Notably, the M proteins of NDV, NiV, HeV, SeV and MuV have also been detected within nucleoli (Pentecost et al, 2015), with nucleolar localization of NiV, HeV, SeV and MuV enhanced by ubiquitin depletion, suggesting that ubiquitination is required for nucleolar egress (Pentecost et al, 2015). Since nuclear and nucleolar localization involve distinct mechanisms [for review, see Rawlinson & Moseley (2015)], this suggests the presence of specific targeting activity within the proteins to enable as yet undefined roles within the nucleolus. Notably, nucleolar interaction by other viruses has been linked to regulation of apoptosis, stress responses and transcription (Rawlinson & Moseley, 2015), such that a major aspect of nuclear localization of certain NSV proteins may relate to modulation of nucleolar functions.…”

“…Since nuclear and nucleolar localization involve distinct mechanisms [for review, see Rawlinson & Moseley (2015)], this suggests the presence of specific targeting activity within the proteins to enable as yet undefined roles within the nucleolus. Notably, nucleolar interaction by other viruses has been linked to regulation of apoptosis, stress responses and transcription (Rawlinson & Moseley, 2015), such that a major aspect of nuclear localization of certain NSV proteins may relate to modulation of nucleolar functions. A recent siRNA screen of HeV infection identified a significant number of nuclear and nucleolar proteins as important to infection, with the most significant effect observed for knockdown of the nucleolar marker fibrillarin, which was also shown to bind to HeV M protein (Deffrasnes et al, 2016).…”