Molecular mechanisms of stress-induced reactivation in mumps virus condensates

Cell, Год журнала: 2023, Номер 186(9), С. 1877 - 1894.e27

Опубликована: Апрель 1, 2023

Negative-stranded RNA viruses can establish long-term persistent infection in the form of large intracellular inclusions human host and cause chronic diseases. Here, we uncover how cellular stress disrupts metastable host-virus equilibrium induces viral replication a culture model mumps virus. Using combination cell biology, whole-cell proteomics, cryo-electron tomography, show that factories are dynamic condensates identify largely disordered phosphoprotein as driver their assembly. Upon stress, increased phosphorylation at its interaction interface with polymerase coincides formation stable complex. By obtaining atomic models for authentic virus nucleocapsid, elucidate concomitant conformational change exposes genome to machinery. These events constitute stress-mediated switch within provide an environment support upregulation replication.

Язык: Английский

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Liquid-liquid phase separation of nucleocapsid proteins during SARS-CoV-2 and HIV-1 replication

Cell Reports, Год журнала: 2022, Номер 42(1), С. 111968 - 111968

Опубликована: Дек. 26, 2022

The leap of retroviruses and coronaviruses from animal hosts to humans has led two ongoing pandemics tens millions deaths worldwide. Retrovirus coronavirus nucleocapsid proteins have been studied extensively as potential drug targets due their central roles in virus replication, among which is capacity bind respective genomic RNAs for packaging into nascent virions. This review focuses on fundamental studies these how intrinsic abilities condense through liquid-liquid phase separation (LLPS) contribute viral replication. Therapeutic targeting condensates methodological advances are also described address future questions contributes

Язык: Английский

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Biomolecular condensates: insights into early and late steps of the HIV-1 replication cycle

Retrovirology, Год журнала: 2023, Номер 20(1)

Опубликована: Апрель 7, 2023

Abstract A rapidly evolving understanding of phase separation in the biological and physical sciences has led to redefining virus-engineered replication compartments many viruses with RNA genomes. Condensation viral, host genomic subgenomic RNAs can take place evade innate immunity response help viral replication. Divergent prompt liquid–liquid (LLPS) invade cell. During HIV there are several steps involving LLPS. In this review, we characterize ability individual partners that assemble into biomolecular condensates (BMCs). Of note, bioinformatic analyses predict models line published observations. Importantly, BMCs contribute function key retroviral For example, reverse transcription takes within nuclear BMCs, called HIV-MLOs while during late steps, nucleocapsid acts as a driver or scaffold recruit client components aid assembly progeny virions. Overall, LLPS infections represents newly described event now appreciated virology field, also be considered an alternative pharmacological target current drug therapies especially when become resistant antiviral treatment.

Язык: Английский

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HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Авг. 25, 2024

Abstract HIV-1 integration favors nuclear speckle (NS)-proximal chromatin and viral infection induces the formation of capsid-dependent CPSF6 condensates that colocalize with speckles (NSs). Although displays liquid-liquid phase separation (LLPS) activity in vitro, contributions its different intrinsically disordered regions, which includes a central prion-like domain (PrLD) capsid binding FG motif C-terminal mixed-charge (MCD), to LLPS remain unclear. Herein, we determined PrLD MCD both contribute vitro. Akin mutant CPSF6, cells expressing MCD-deleted uncharacteristically arrested at rim. While heterologous MCDs effectively substituted for function during infection, Arg-Ser domains from related SR proteins were largely ineffective. wildtype displayed similar affinities, imparted LLPS-dependent higher-order co-aggregation capsids vitro cellulo. NS depletion reduced puncta without significantly affecting into NS-proximal chromatin, appending onto protein partially restored virus penetration targeting knockout cells. We conclude MCD-dependent condensation underlies post-nuclear incursion DNA pathogenesis.

Язык: Английский

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RNA and condensates: Disease implications and therapeutic opportunities

Cell chemical biology, Год журнала: 2024, Номер 31(9), С. 1593 - 1609

Опубликована: Сен. 1, 2024

Язык: Английский

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HIV-Induced CPSF6 Condensates

Journal of Molecular Biology, Год журнала: 2023, Номер 435(16), С. 168094 - 168094

Опубликована: Апрель 14, 2023

Язык: Английский

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Biomolecular phase separation in stress granule assembly and virus infection

Acta Biochimica et Biophysica Sinica, Год журнала: 2023, Номер 55(7), С. 1099 - 1118

Опубликована: Июнь 14, 2023

Liquid-liquid phase separation (LLPS) has emerged as a crucial mechanism for cellular compartmentalization. One prominent example of this is the stress granule. Found in various types cells, granule biomolecular condensate formed through separation. It comprises numerous RNA and RNA-binding proteins. Over past decades, substantial knowledge been gained about composition dynamics granules. SGs can regulate signaling pathways have associated with human diseases, such neurodegenerative cancer, infectious diseases. The threat viral infections continues to loom over society. Both DNA viruses depend on host cells replication. Intriguingly, many stages life cycle are closely tied metabolism cells. field condensates rapidly advanced recent times. In context, we aim summarize research granules their link infections. Notably, triggered by behave differently from canonical sodium arsenite (SA) heat shock. Studying context could offer valuable platform replication processes anti-viral responses. A deeper understanding these biological pave way innovative interventions treatments They potentially bridge gap between basic interactions hosts.

Язык: Английский

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Abnormal phase separation of biomacromolecules in human diseases

Acta Biochimica et Biophysica Sinica, Год журнала: 2023, Номер 55(7), С. 1133 - 1152

Опубликована: Июль 1, 2023

Membrane-less organelles (MLOs) formed through liquid-liquid phase separation (LLPS) are associated with numerous important biological functions, but the abnormal will also dysregulate physiological processes. Emerging evidence points to importance of LLPS in human health and diseases. Nevertheless, despite recent advancements, our knowledge molecular relationship between diseases is frequently incomplete. In this review, we outline current understanding about how aberrant affects developmental disorders, tandem repeat cancers viral infection. We examine disease mechanisms driven by condensates, highlight potential treatment approaches. This study seeks expand providing a valuable new paradigm for as well further translate regarding into therapeutic discoveries.

Язык: Английский

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Revolutionizing viral disease treatment: Phase separation and lysosome/exosome targeting as new areas and new paradigms for antiviral drug research

Drug Discovery Today, Год журнала: 2024, Номер 29(3), С. 103888 - 103888

Опубликована: Янв. 21, 2024

Язык: Английский

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Membraneless Organelles and Condensates Orchestrate Innate Immunity Against Viruses

Journal of Molecular Biology, Год журнала: 2023, Номер 435(16), С. 167976 - 167976

Опубликована: Янв. 23, 2023

Язык: Английский

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