Deciphering Phase-Separated Mitochondrial RNA Granules under Stress Conditions with the Mitoribosome-Targeting Small Molecule DOI

Gui-Xue Tang,

Shu-Tang Zeng,

Jian Wang

et al.

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

RNA granules are liquid-liquid-phase-separated condensates comprising and proteins. Despite growing insights into their biological functions, studies have predominantly relied on methodologies lacking adequate chemical tools. Here, we introduce ICP-CHARGINGS, a concept for efficiently identifying probes to characterize of interest among nucleic acid-targeting agents. Focusing mitochondrial (MRGs), whose functions remain elusive, developed methodology within this framework identified NATA, new fluorescent molecule that, following mechanistic studies, was found bind the mitoribosome, enabling MRG labeling recognition. Using NATA reveal potential buffering roles MRGs, demonstrated close correlation between maintenance assembly cellular survival proliferation under cold shock hypoxic stress. Overall, introduction implementation ICP-CHARGINGS strategy provide specialized tool advancing our comprehension biology establish paradigm elucidating structures that can be targeted by small molecules, paving way developing tailored diverse in future research.

Language: Английский

Fundamental Aspects of Phase-Separated Biomolecular Condensates DOI
Huan‐Xiang Zhou,

Divya Kota,

Sanbo Qin

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8550 - 8595

Published: June 17, 2024

Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations behaviors properties biomolecular condensates. Here we aim fill this by writing a comprehensive, critical, accessible review on fundamental aspects phase-separated We introduce relevant theoretical background, present basis for computation experimental measurement condensate properties, give mechanistic interpretations terms interactions at molecular residue levels.

Language: Английский

Citations

22
The RNA binding protein EHD6 recruits the m6A reader YTH07 and sequesters OsCOL4 mRNA into phase-separated ribonucleoprotein condensates to promote rice flowering DOI Creative Commons

Song Cui,

Peizhe Song, Chaolong Wang

et al.

Molecular Plant, Journal Year: 2024, Volume and Issue: 17(6), P. 935 - 954

Published: May 7, 2024

N

Language: Английский

Citations

17
Martini3-IDP: improved Martini 3 force field for disordered proteins DOI Creative Commons
Liguo Wang, Christopher Brasnett, Luís Borges-Araújo

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 24, 2025

Coarse-grained (CG) molecular dynamics (MD) is widely used for the efficient simulation of intrinsically disordered proteins (IDPs). The Martini model, one most popular CG force fields in biomolecular simulation, was reported to yield too compact IDP conformations, limiting its applications. Addressing this, we optimized bonded parameters based on fitting reference simulations a diverse set IDPs at atomistic resolution, resulting Martini3-based protein model coined Martini3-IDP. This leads expanded greatly improving reproduction experimentally measured radii gyration. Moreover, contrary ad-hoc fixes scaling protein-protein or protein-water interactions, Martini3-IDP keeps overall interaction balance underlying 3. To validate that, perform comprehensive testing including full-length multidomain proteins, IDP-lipid membrane binding and IDP-small molecule binding, confirming ability successfully capture complex interplay between components. Finally, recently emerging concept condensate, through liquid-liquid phase separation, also reproduced by number both homotypic heterotypic systems. With improved expand simulate processes involving environments, spatio-temporal scales inaccessible with all-atom models. Here, authors introduce Martini3-IDP, refined that addresses prior over-compact structures. Validated across systems, it captures interactions condensates.

Language: Английский

Citations

2
RNA-driven phase transitions in biomolecular condensates DOI
Gable M. Wadsworth, Sukanya Srinivasan, Lien B. Lai

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(19), P. 3692 - 3705

Published: Oct. 1, 2024

Language: Английский

Citations

14
Extracellular vesicles, RNA sequencing, and bioinformatic analyses: Challenges, solutions, and recommendations DOI Creative Commons
Rebecca T. Miceli,

Tzu-yi Chen,

Yohei Nose

et al.

Journal of Extracellular Vesicles, Journal Year: 2024, Volume and Issue: 13(12)

Published: Dec. 1, 2024

Abstract Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs other molecular footprints from cell of origin, thus have evident applications in liquid biopsy, therapeutics, intercellular communication. Yet, the complete transcriptomic landscape is poorly characterized due to critical limitations including variable protocols used for EV‐RNA extraction, quality control, cDNA library preparation, sequencing technologies, bioinformatic analyses. Consequently, there a gap knowledge need standardized approach delineating EV‐RNAs. Here, we address these gaps describing following points (1) focusing on large canopy particles (EVPs), which includes, but not limited – exosomes EVs, lipoproteins, exomeres/supermeres, mitochondrial‐derived vesicles, RNA binding proteins, cell‐free DNA/RNA/proteins; (2) examining potential roles biogenesis EVPs; (3) discussing various methods technologies uncovering cargoes (4) presenting comprehensive list subtypes reported (5) different databases resources specific species; (6) reviewing established bioinformatics pipelines novel strategies reproducible EV transcriptomics analyses; (7) emphasizing significant gold standard identifying EV‐RNAs across studies; (8) finally, highlight current challenges, discuss possible solutions, present recommendations robust analyses EVP‐associated RNAs. Overall, seek provide clarity landscape, EVP‐RNAs. Detailed portrayal state EVP will lead better understanding how cargo EVPs can be modern targeted diagnostics therapeutics. For inclusion discussed this article, use terms large/small non‐vesicular extracellular (NVEPs), EPs as defined MISEV guidelines International Society Vesicles (ISEV).

Language: Английский

Citations

14
Friend or foe: The role of stress granule in neurodegenerative disease DOI

Qinqin Cui,

Zhongyi Liu,

Ge Bai

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2464 - 2485

Published: May 13, 2024

Language: Английский

Citations

12
µMap proximity labeling in living cells reveals stress granule disassembly mechanisms DOI
Chenmengxiao Pan, Steve D. Knutson, Sean W. Huth

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

Language: Английский

Citations

12
Annexin A11 aggregation in FTLD–TDP type C and related neurodegenerative disease proteinopathies DOI Creative Commons
John Robinson,

EunRan Suh,

Yan Xu

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: June 1, 2024

Abstract TAR DNA-binding protein 43 (TDP-43) is an RNA binding found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with (FTLD–TDP) and limbic predominant age-related encephalopathy neuropathologic change (LATE-NC). Annexin A11 also known form aggregates ALS cases pathogenic variants ANXA11 . aggregation has not been described sporadic ALS, FTLD–TDP or LATE-NC cases. To explore the relationship between A11, genetic analysis of 822 autopsy was performed identify rare variants. In addition, immunohistochemical study 368 aggregates. Insoluble which colocalize were present all Type C seen a small proportion (3–6%) types A B, LATE-NC. we confirm comingling case p.G38R variant. Finally, abundant as primary pathologic finding progressive supranuclear palsy-like dementia prominent striatal vacuolization due novel variant, p.P75S. By immunoblot, annexinopathy variant show accumulation insoluble truncated fragment. These results indicate that diverse heterogeneous range both proteinopathies. vacuolar p.P75S suggests sufficient cause neurodegeneration.

Language: Английский

Citations

11
Phase Separation Modulates the Thermodynamics and Kinetics of RNA Hybridization DOI
Atul Rangadurai,

Lisa Ruetz,

Rashik Ahmed

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(29), P. 19686 - 19689

Published: July 11, 2024

Biomolecular condensates can influence cellular function in a number of ways, including by changing the structural dynamics and conformational equilibria molecules partitioned within them. Here we use methyl transverse relaxation optimized spectroscopy (methyl-TROSY) NMR conjunction with 2'-

Language: Английский

Citations

9
Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors DOI Creative Commons
Shashank Shekhar, Charles Tracy, Peter V. Lidsky

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction the integrated stress response (ISR) deep in brain, indicated by eIF2αS50 phosphorylation-dependent elevated levels ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, XRP1 transcription enriched cytosolic granules that positive RNA granule markers Caprin, FMR1, p62, reversible upon restoration vision blind flies. Cytosolic restraint dampens expression their downstream targets including genes cell death pathways activated chronic cellular thus constitutes a protective (CSPR). containing both p62 also evident thalamus hippocampus mouse congenital or degenerative blindness. These data indicate conserved link between input curbed responses critical protein quality control brain. Chronic can be damaging hazards they counteract. Here authors show how blindness-induced brain-wide is dampened sequestration granules.

Language: Английский

Citations

1