TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Abstract Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected host-mediated post-translational modifications. Here, we demonstrate that SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby innate antiviral immune response suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation a newly identified SUMO-interacting motif SARS2-NP. Importantly, widespread SARS2-NP R203K mutation gains novel site SUMOylation further increases LLPS immunosuppression. Notably, E3 ligase TRIM28 responsible for catalyzing SUMOylation. An interfering peptide targeting interaction was screened out block LLPS, consequently inhibit replication rescue immunity. Collectively, these data critical virulence, therefore provide strategy antagonize SARS-CoV-2.

Language: Английский

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Phase separation in viral infections

Trends in Microbiology, Journal Year: 2022, Volume and Issue: 30(12), P. 1217 - 1231

Published: July 25, 2022

Language: Английский

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Liquid Phase Partitioning in Virus Replication: Observations and Opportunities

Annual Review of Virology, Journal Year: 2022, Volume and Issue: 9(1), P. 285 - 306

Published: June 16, 2022

Viruses frequently carry out replication in specialized compartments within cells. The effect of these structures on virus is poorly understood. Recent research supports phase separation as a foundational principle for organization cellular components with the potential to influence viral replication. In this review, described context formation centers, an emphasis nonsegmented negative-strand RNA viruses. Consideration given interplay between and critical processes transcription genome replication, role regions pathogen-host interactions discussed. Finally, questions that must be addressed fully understand how influences life cycle are presented, along information about new approaches could used make important breakthroughs emerging field.

Language: Английский

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Liquid-liquid Phase Separation in Viral Function

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(16), P. 167955 - 167955

Published: Jan. 13, 2023

Language: Английский

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Co‐opted cytosolic proteins form condensate substructures within membranous replication organelles of a positive‐strand RNA virus

New Phytologist, Journal Year: 2024, Volume and Issue: 243(5), P. 1917 - 1935

Published: March 21, 2024

Summary Positive‐strand RNA viruses co‐opt organellar membranes for biogenesis of viral replication organelles (VROs). Tombusviruses also pro‐viral cytosolic proteins to VROs. It is currently not known what type molecular organization keeps co‐opted sequestered within membranous In this study, we employed tomato bushy stunt virus (TBSV) and carnation Italian ringspot (CIRV) – Nicotiana benthamiana pathosystems identify biomolecular condensate formation in We show that TBSV p33 the CIRV p36 sequester glycolytic fermentation enzymes unique substructures associated with find form droplets vitro driven by intrinsically disordered region. The protein organizes partitioning host into droplets. VRO‐associated condensates are critical local adenosine triphosphate production support energy replication. endoplasmic reticulum actin filaments meshworks around VRO condensates, contributing composition structure. propose p33/p36 organize liquid–liquid phase separation concentrated Overall, demonstrate subverted co‐exist functions. induce connect two

Language: Английский

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

Cell Reports, Journal Year: 2022, Volume and Issue: 42(1), P. 111968 - 111968

Published: Dec. 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

Language: Английский

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Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(13), P. 5103 - 5122

Published: Jan. 1, 2022

Cancer is a public health problem of great concern, and it also one the main causes death in world.Cancer disease characterized by dysregulation diverse cellular processes, including avoiding growth inhibitory factors, immune damage promoting metastasis, etc.However, precise mechanism tumorigenesis tumor progression still needs to be further elucidated.Formations liquid-liquid phase separation (LLPS) condensates are common strategy for cells achieve functions, such as chromatin organization, signal transduction, DNA repair transcriptional regulation, etc.The biomolecular aggregates formed LLPS mainly driven multivalent weak interactions mediated intrinsic disordered regions (IDRs) proteins.In recent years, aberrant separations transition have been reported related process various diseases, neurodegenerative diseases cancer.Herein, we discussed findings that regulates tumor-related signaling pathways thus contributes progression.We reviewed some virus-associated proteins regulate development tumors via separation.Finally, possible strategies treating targeting separation.

Language: Английский

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Defining basic rules for hardening influenza A virus liquid condensates

eLife, Journal Year: 2023, Volume and Issue: 12

Published: April 4, 2023

In biological systems, liquid and solid-like biomolecular condensates may contain the same molecules but their behaviour, including movement, elasticity, viscosity, is different on account of distinct physicochemical properties. As such, it known that phase transitions affect function material properties can be tuned by several factors temperature, concentration, valency. It is, however, unclear if some are more efficient than others at regulating behaviour. Viral infections good systems to address this question as they form de novo part replication programmes. Here, we used influenza A virus (IAV) cytosolic condensates, AKA viral inclusions, provide a proof concept condensate hardening via changes in valency its components altering concentration or temperature cell. Liquid IAV inclusions hardened targeting vRNP (viral ribonucleoprotein) interactions NP (nucleoprotein) oligomerising molecule, nucleozin, both vitro vivo without affecting host proteome abundance nor solubility. This study starting point for understanding how pharmacologically modulate offer opportunities alternative antiviral strategies.

Language: Английский

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

Retrovirology, Journal Year: 2023, Volume and Issue: 20(1)

Published: April 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.

Language: Английский

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Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS‐CoV‐2 nucleocapsid protein and its liquid–liquid phase separation

Journal of Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 125(3)

Published: Feb. 13, 2024

Abstract When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has wide spectrum of clinical manifestations, from no symptoms acute respiratory distress syndrome. The initiates damage by attaching ACE‐2 protein on surface endothelial cells line blood vessels and using these as hosts for replication. Reactive oxygen species levels are increased during viral replication, which oxidative stress. About three‐fifths (~60%) people who get infected with eradicate their body after 28 days recover normal activity. However, large fraction (~40%) suffer various (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, tachycardia) beyond 12 weeks diagnosed syndrome long COVID. Long‐term studies in group contracted have been contrasted noninfected matched people. A subset can be distinguished set cytokine markers persistent, low‐grade inflammation often self‐report two or more bothersome symptoms. No medication alleviate efficiently. Coronavirus nucleocapsid proteins investigated extensively potential drug targets due key roles among is ability bind respective genomic RNAs incorporation into emerging virions. This review highlights basic its undergo liquid–liquid phase separation. We hypothesize this separation may contribute hypothesis unlocks new investigation angles could potentially open novel avenues better understanding COVID treating condition.

Language: Английский

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