Negri bodies and other virus membrane-less replication compartments

Abstract

Viruses reshape the organization of the cell interior to achieve different steps of their cellular cycle. Particularly, viral replication and assembly often take place in viral factories where specific viral and cellular proteins as well as nucleic acids concentrate. Viral factories can be either membrane-delimited or devoid of any cellular membranes. In the latter case, they are referred as membrane-less replication compartments. The most emblematic ones are the Negri bodies, which are inclusion bodies that constitute the hallmark of rabies virus infection. Interestingly, Negri bodies and several other viral replication compartments have been shown to arise from a liquid-liquid phase separation process and, thus, constitute a new class of liquid organelles. This is a paradigm shift in the field of virus replication. Here, we review the different aspects of membrane-less virus replication compartments with a focus on the Mononegavirales order and discuss their interactions with the host cell machineries and the cytoskeleton. We particularly examine the interplay between viral factories and the cellular innate immune response, of which several components also form membrane-less condensates in infected cells.

Liquid–Liquid Phase Separation by Intrinsically Disordered Protein Regions of Viruses: Roles in Viral Life Cycle and Control of Virus–Host Interactions

“…Co-expression of N and P proteins from paramyxoviruses also leads to the appearance in transfected cells of spherical inclusions that recapitulate the liquid properties of IBs. In all cases, the protein regions required for IBs formation are intrinsically disordered (for reviews see [182] and [183]). In the case of Borna disease virus (BDV, another member of the Mononegavirales order), the P protein alone is sufficient to sustain the formation of IBs with a probable liquid nature [184].…”

Liquid Biomolecular Condensates and Viral Lifecycles: Review and Perspectives

“…In fact, the ability to undergo LLPS does not require conservation at the level of the amino acid sequence but rather summing a series of characteristics, including possessing IDR, LCR, and/or RNA binding domains. Interestingly, and in a broader sense, many unrelated viruses are capable of forming replication-like factories whose assembly is, at least partially, driven by their genomecoating proteins [23,28,31]. The next few years will certainly provide understanding on how LLPS operates in transcription/replication in viral-infected cells.…”

“…Finally, many other viruses were shown to form membraneless organelles. Examples include DNA viruses such as Herpesviridae, Papillomaviridae, Adenoviridae, Parvoviridae, and Polyomaviridae that replicate in the nucleus or Poxviridae, Iridoviridae, and Asfaviridae that replicate in the cytosol [13,31]. Whether any of these viruses assemble organelles with liquid-like behavior and whether LLPS is involved in their lifecycles remains to be elucidated.…”

“…Studies exploring biomolecular condensates in viral infections have relied on two approaches: investigating if viral proteins undergo LLPS in minimalist in vitro assays, as seen for SARS-CoV-2 [27,32,163,170] or HIV [35], or using cells to provide descriptive accounts of the liquid behavior of biomolecular condensates [22][23][24]26,28,30,31,219], without understanding if the formation of these structures is governed by LLPS. In fact, liquid-like replication compartments built during Herpes Simplex Virus 1 behave in ways that are not consistent with LLPS principles [220].…”

Formation and Function of Liquid-Like Viral Factories in Negative-Sense Single-Stranded RNA Virus Infections

“…Unfortunately, only a few host proteins have been identified within NNS RNA IBs, partially due to their lack of an enclosing membrane and hence the technical challenge of IB purification. Moreover, host proteins so far identified are seemingly diverse and lack a commonality among different viruses [ 75 ]. Proteomic identification of IB-associated host factors (e.g., via the APEX-based [ 76 , 77 ] or BioID-based [ 78 , 79 ] labeling) and characterization of their roles in modulating the structure and function of IBs represent top priorities.…”