A compositional view comparing modern biological condensates and primitive phase‐separated compartments DOI Creative Commons
Selene M. C. Cannelli, R. S. Gupta, Tan Dat Nguyen

et al.

Peptide Science, Journal Year: 2023, Volume and Issue: 115(6)

Published: Aug. 30, 2023

Abstract Liquid–liquid phase separation (LLPS) is a process that often occurs due to binding between oppositely charged biopolymers, and has gained increasing attention recently their ubiquity in biological systems ability direct essential cellular processes. However, while these discoveries biology are recent, the field of origins life been investigating LLPS for nearly 100 years, ever since first suggestions by Oparin Haldane primitive could have precursors cells on Earth. Since then, significant amount work done elucidate different relevant as protocellular models. Given structural similarities modern membraneless organelles, there may even be an evolutionary link two, although this remains question answered. Nevertheless, order answer this, source compares compositional aspects condensates necessary. Here, we focus organelles composed intrinsically disordered proteins (IDPs) nucleic acids. Then, parallel, explore compartments simple biopolymers such short peptides This followed discussion how biomolecules Earth originated, analyzing environmental chemical conditions favored Finally, directly compare composition phase‐separated compartments, further discussing potential IDPs early Earth, but also evolution from membrane‐bound cells. review aims provide comparison structures help researchers both fields understand current state knowledge, knowledge evolved, gaps need addressed.

Language: Английский

Interactions between the picornavirus 3C(D) main protease and RNA induce liquid-liquid phase separation DOI Creative Commons
Somnath Mondal, Saumyak Mukherjee, Kevin Namitz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

ABSTRACT The picornavirus 3CD protein is a precursor to the 3C main protease and 3D RNA-dependent RNA polymerase. In addition its functions in proteolytic processing of virus polyprotein cleavage key host factors, domain interacts with cis-acting replication elements (CREs) within viral genome regulate translation events. We investigated molecular determinants binding using wide range biophysical computational methods. These studies showed that binds broad spectrum oligonucleotides, displaying minimal dependence on sequence structure. However, they also uncovered novel aspect these interactions, is, 3C-RNA can induce liquid-liquid phase separation (LLPS), 3CD-RNA interactions likewise leading LLPS. This may be general phenomenon for other 3C-like proteases, incorporating domains. findings have potential implications understanding virally induced apoptosis controlling stress granules, which involve LLPS include proteins known 3C/3CD.

Language: Английский

Citations

0
Phase separation in DNA repair: orchestrating the cellular response to genomic stability DOI Creative Commons
Jinghao Deng, Zhiping Du, Lei Li

et al.

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e19402 - e19402

Published: May 2, 2025

DNA repair is a hierarchically organized, spatially and temporally regulated process involving numerous factors that respond to various types of damage. Despite decades research, the mechanisms by which these are recruited depart from sites have been subject intrigue. Recent advancements in field increasingly highlighted role phase separation as critical facilitator efficiency repair. This review emphasizes how enhances concentration coordination at damage sites, optimizing efficiency. Understanding dysregulation can impair alter nuclear organization, potentially leading diseases such cancer neurodegenerative disorders, crucial. manuscript provides comprehensive understanding pivotal repair, sheds light on current suggests potential future directions for research therapeutic interventions.

Language: Английский

Citations

0
Liaisons dangereuses: Intrinsic Disorder in Cellular Proteins Recruited to Viral Infection-Related Biocondensates DOI Open Access
Greta Bianchi, Stefania Brocca, Sonia Longhi

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2151 - 2151

Published: Jan. 21, 2023

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

Language: Английский

Citations

9
The Formation and Function of Birnaviridae Virus Factories DOI Open Access
Andrew J. Brodrick, Andrew J. Broadbent

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8471 - 8471

Published: May 9, 2023

The use of infectious bursal disease virus (IBDV) reverse genetics to engineer tagged reporter viruses has revealed that the factories (VFs) Birnaviridae family are biomolecular condensates show properties consistent with liquid–liquid phase separation (LLPS). Although VFs not bound by membranes, it is currently thought viral protein 3 (VP3) initially nucleates formation VF on cytoplasmic leaflet early endosomal and likely drives LLPS. In addition VP3, IBDV contain VP1 (the polymerase) dsRNA genome, they sites de novo RNA synthesis. Cellular proteins also recruited VFs, which provide an optimal environment for replication; grow due synthesis components, recruitment other proteins, coalescence multiple in cytoplasm. Here, we review what known about formation, properties, composition, processes these structures. Many open questions remain regarding biophysical nature as well roles play replication, translation, virion assembly, genome partitioning, modulating cellular processes.

Language: Английский

Citations

9
Cellular nucleic acid-binding protein restricts SARS-CoV-2 by regulating interferon and disrupting RNA–protein condensates DOI Creative Commons
Yongzhi Chen, Xuqiu Lei, Zhaozhao Jiang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(47)

Published: Nov. 14, 2023

A detailed understanding of the innate immune mechanisms involved in restricting SARS-CoV-2 infection and how virus disrupts these processes could reveal new strategies to boost antiviral develop therapeutics for COVID-19. Here, we identify cellular nucleic acid-binding protein (CNBP) as a key host factor controlling infection. In response RNA-sensing pathways, CNBP is phosphorylated translocates from cytosol nucleus where it binds interferon-β enhancer initiate transcription. Because evades detection by host’s largely retained restricts directly, leading battle between that extends beyond signaling pathways. We further demonstrated viral RNA directly competes with nucleocapsid prevent forming liquid–liquid phase separation (LLPS) condensates critical replication. Consequently, cells animals lacking have higher loads, CNBP-deficient mice succumb rapidly Altogether, findings SARS-CoV-2, functioning both regulator IFN gene expression cell-intrinsic restriction LLPS limit replication spread. addition, our studies also highlight important targets development drugs combat

Language: Английский

Citations

9
Biomolecular Condensates as Novel Antiviral Targets DOI Open Access
Erik Martin, Christiane Iserman, Balaji Olety

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 436(4), P. 168380 - 168380

Published: Dec. 5, 2023

Language: Английский

Citations

9
Liquid-liquid phase separation: a new perspective on respiratory diseases DOI Creative Commons
Li Wang, Yongjun Wang, Z. J. Ke

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 26, 2024

Liquid-liquid phase separation (LLPS) is integral to various biological processes, facilitating signal transduction by creating a condensed, membrane-less environment that plays crucial roles in diverse physiological and pathological processes. Recent evidence has underscored the significance of LLPS human health disease. However, its implications respiratory diseases remain poorly understood. This review explores current insights into mechanisms LLPS, focusing particularly on relevance diseases, aiming deepen our understanding propose new paradigm for studying this context.

Language: Английский

Citations

3
Hardening of Respiratory Syncytial Virus Inclusion Bodies by Cyclopamine Proceeds through Perturbation of the Interactions of the M2-1 Protein with RNA and the P Protein DOI Open Access
Cédric Diot, Charles-Adrien Richard, Jennifer Risso-Ballester

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 13862 - 13862

Published: Sept. 8, 2023

Respiratory syncytial virus (RSV) RNA synthesis takes place in cytoplasmic viral factories also called inclusion bodies (IBs), which are membrane-less organelles concentrating the polymerase complex. The assembly of IBs is driven by liquid-liquid phase separation promoted interactions between nucleoprotein N and phosphoprotein P. We recently demonstrated that cyclopamine (CPM) inhibits RSV multiplication disorganizing hardening IBs. Although a single mutation transcription factor M2-1 induced resistance to CPM, mechanism action CPM still remains be characterized. Here, using FRAP experiments on reconstituted pseudo-IBs both cellula vitro, we first activity depends presence together with showed impairs competition P binding M2-1. As mutations against activity, suggest may affect dynamics M2-1-P interaction, thereby affecting relative mobility proteins contained Overall, our results reveal stabilizing protein-protein an attractive new antiviral approach. They pave way for rational chemical optimization specific anti-RSV molecules.

Language: Английский

Citations

7
Comprehensive analysis of liquid–liquid phase separation propensities of HSV‐1 proteins and their interaction with host factors DOI Creative Commons
Sushma Subedi, Niharika Nag, Harish Shukla

et al.

Journal of Cellular Biochemistry, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 5, 2023

Abstract In recent years, it has been shown that the liquid–liquid phase separation (LLPS) of virus proteins plays a crucial role in their life cycle. It promotes formation viral replication organelles, concentrating components for efficient and facilitates assembly particles. LLPS emerged as process herpes simplex virus‐1 (HSV‐1). Recent studies have identified several HSV‐1 involved LLPS, including myristylated tegument protein UL11 infected cell 4; however, complete proteome‐level understanding LLPS‐prone is not available. We provide comprehensive analysis proteome explore potential its to undergo LLPS. By integrating sequence analysis, prediction algorithms an array tools servers, we 10 exhibit high potential. analysing amino acid sequences proteins, specific motifs enriched residues commonly found regions. Our findings reveal diverse range within HSV‐1, which are critical processes such replication, transcriptional regulation This suggests might play facilitating specialized compartments virion. The identification opens up new avenues molecular mechanisms underlying pathogenesis. work provides valuable insights into landscape highlighting targets further experimental validation enhancing our

Language: Английский

Citations

7
The Rous sarcoma virus Gag Polyprotein Forms Biomolecular Condensates Driven by Intrinsically-disordered Regions DOI Creative Commons
Rebecca J. Kaddis Maldonado, Gregory S. Lambert, Breanna L. Rice

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(16), P. 168182 - 168182

Published: June 15, 2023

Language: Английский

Citations

7