Abstract
Liquid–liquid phase separation (LLPS) represents a major physiochemical principle to organize intracellular membrane-less structures. Studies with non-segmented negative-sense (NNS) RNA viruses have uncovered a key role of LLPS in the formation of viral inclusion bodies (IBs), sites of viral protein concentration in the cytoplasm of infected cells. These studies further reveal the structural and functional complexity of viral IB factories and provide a foundation for their future research. Herein, we review the literature leading to the discovery of LLPS-driven formation of IBs in NNS RNA virus-infected cells and the identification of viral scaffold components involved, and then outline important questions and challenges for IB assembly and disassembly. We discuss the functional implications of LLPS in the life cycle of NNS RNA viruses and host responses to infection. Finally, we speculate on the potential mechanisms underlying IB maturation, a phenomenon relevant to many human diseases.
Highlights
Among all virus taxa, the phylum Negarnaviricota embodies all viruses with RNA genomes of negative polarity [1]
As a hallmark of infection by NNS RNA viruses, the formation of inclusion bodies (IBs) is observed in the cytoplasm of cells infected by paramyxoviruses (e.g., measles virus (MeV) [53,54], mumps virus (MuV) [55], Nipah virus (NiV) [56], parainfluenza virus type 3 (PIV3) [57], and parainfluenza virus type 5 (PIV5) [58]), pneumoviruses (e.g., respiratory syncytial virus (RSV) [59] and human metapneumovirus (HMPV) [60]), rhabdoviruses (e.g., rabies virus (RABV) [61] and vesicular stomatitis virus (VSV) [62]), and filoviruses (e.g., Marburg virus (MARV) [63] and Ebola virus (EBOV) [64])
Using MeV as a model system, we have found that the IB size is reduced by adding a casein kinase 2 (CK2) inhibitor or mutating the two major CK2 phosphorylation sites of P protein [70]
Summary
The phylum Negarnaviricota embodies all viruses with RNA genomes of negative polarity [1]. Structural studies have been conducted to characterize viral RNPs for several NNS RNA viruses, including vesicular stomatitis virus (VSV) [3], rabies virus (RABV) [4], respiratory syncytial virus (RSV) [5], parainfluenza virus type 5 (PIV5) [6], and Ebola virus (EBOV) [7]. Upon infection by these mononegaviruses, viral macromolecular synthesis is cytoplasmic (with exception of Bornaviridae where it is nuclear). While the field awaits consensus of a new nomenclature, we will adopt the conventional terminology throughout the article
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