When liquid-liquid phase separation meets viral infections

Wei, Wenqiang; Bai, Lu; Yan, Bing; Meng, Weiquan; Wang, Hongju; Zhai, Jingbo; Si, Fusheng; Zheng, Chunfu

doi:10.3389/fimmu.2022.985622

Cited by 20 publications

(26 citation statements)

References 101 publications

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“…It has been increasingly appreciated that BMCs play an important role the replication of many viruses, including influenza, SARS-CoV-2, HIV-1, and others, as reviewed elsewhere [81][82][83][84]. In our previous work, we observed the in vivo formation of RSV Gag foci in the nucleus, cytoplasm, and plasma membrane that colocalize with unspliced viral RNA and splicing factors [3,4,23].…”

Section: Discussionmentioning

confidence: 71%

The Rous sarcoma virus Gag polyprotein forms biomolecular condensates driven by intrinsically-disordered regions

Maldonado

Rice

Lambert

et al. 2023

Preprint

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Biomolecular condensates (BMCs) play important roles in cellular structures including transcription factories, splicing speckles, and nucleoli. BMCs bring together proteins and other macromolecules, selectively concentrating them so that specific reactions can occur without interference from the surrounding environment. BMCs are often made up of proteins that contain intrinsically disordered regions (IDRs), form phase-separated spherical puncta, form liquid-like droplets that undergo fusion and fission, contain molecules that are mobile, and are disrupted with phase-dissolving drugs such as 1,6-hexanediol. In addition to cellular proteins, many viruses, including influenza A, SARS-CoV-2, and human immunodeficiency virus type 1 (HIV-1) encode proteins that undergo phase separation and rely on BMC formation for replication. In prior studies of the retrovirus Rous sarcoma virus (RSV), we observed that the Gag protein forms discrete spherical puncta in the nucleus, cytoplasm, and at the plasma membrane that co-localize with viral RNA and host factors, raising the possibility that RSV Gag forms BMCs that participate in the virion intracellular assembly pathway. In our current studies, we found that Gag contains IDRs in the N-terminal (MAp2p10) and C-terminal (NC) regions of the protein and fulfills many criteria of BMCs. Although the role of BMC formation in RSV assembly requires further study, our results suggest the biophysical properties of condensates are required for the formation of Gag complexes in the nucleus and the cohesion of these complexes as they traffic through the nuclear pore, into the cytoplasm, and to the plasma membrane, where the final assembly and release of virus particles occurs.

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Section: Discussionmentioning

confidence: 71%

The Rous sarcoma virus Gag polyprotein forms biomolecular condensates driven by intrinsically-disordered regions

Maldonado

Rice

Lambert

et al. 2023

Preprint

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“…These factories are membraneless structures that have biophysical properties of biomolecular condensates, and emerging evidence suggests that some are nucleated via the process of LLPS ( 40 , 41 ). Hallmarks of LLPS are the formation of spherical droplets through phase separation of proteins and/or nucleic acid ( 42 ). The droplets are dynamic and fuse together over time, allowing the virus to accumulate and consolidate needed resources ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hallmarks of LLPS are the formation of spherical droplets through phase separation of proteins and/or nucleic acid ( 42 ). The droplets are dynamic and fuse together over time, allowing the virus to accumulate and consolidate needed resources ( 42 ). Indeed, it has been shown that RV viroplasms are biomolecular condensates formed in part by the phase separation of non-structural proteins NSP2 and NSP5 ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

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Flexibility of the Rotavirus NSP2 C-Terminal Region Supports Factory Formation via Liquid-Liquid Phase Separation

Nichols

Nilsson

Brown-Harding

et al. 2023

J Virol

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“…LLPS provides an excellent solution to the problem of physical and functional separation of viral macromolecules from those endogenous to the host cell in its cytosol. Accordingly, LLPS has emerged as a new promising target for antiviral approaches [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates

Bianchi

Brocca

Longhi

et al. 2023

IJMS

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Liquid–liquid phase separation (LLPS) is responsible for the formation of so-called membrane-less organelles (MLOs) that are essential for the spatio-temporal organization of the cell. Intrinsically disordered proteins (IDPs) or regions (IDRs), either alone or in conjunction with nucleic acids, are involved in the formation of these intracellular condensates. Notably, viruses exploit LLPS at their own benefit to form viral replication compartments. Beyond giving rise to biomolecular condensates, viral proteins are also known to partition into cellular MLOs, thus raising the question as to whether these cellular phase-separating proteins are drivers of LLPS or behave as clients/regulators. Here, we focus on a set of eukaryotic proteins that are either sequestered in viral factories or colocalize with viral proteins within cellular MLOs, with the primary goal of gathering organized, predicted, and experimental information on these proteins, which constitute promising targets for innovative antiviral strategies. Using various computational approaches, we thoroughly investigated their disorder content and inherent propensity to undergo LLPS, along with their biological functions and interactivity networks. Results show that these proteins are on average, though to varying degrees, enriched in disorder, with their propensity for phase separation being correlated, as expected, with their disorder content. A trend, which awaits further validation, tends to emerge whereby the most disordered proteins serve as drivers, while more ordered cellular proteins tend instead to be clients of viral factories. In light of their high disorder content and their annotated LLPS behavior, most proteins in our data set are drivers or co-drivers of molecular condensation, foreshadowing a key role of these cellular proteins in the scaffolding of viral infection-related MLOs.

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When liquid-liquid phase separation meets viral infections

Cited by 20 publications

References 101 publications

The Rous sarcoma virus Gag polyprotein forms biomolecular condensates driven by intrinsically-disordered regions

The Rous sarcoma virus Gag polyprotein forms biomolecular condensates driven by intrinsically-disordered regions

Flexibility of the Rotavirus NSP2 C-Terminal Region Supports Factory Formation via Liquid-Liquid Phase Separation

Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates

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