Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases DOI
Kalpshree Gogte, Fatemeh Mamashli, María Georgina Herrera

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 122(1)

Published: Dec. 31, 2024

Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein in cellular context incompletely understood. Here, we show that two-dimensional confinement imposed by membrane anchor stabilizes native conformation suppresses liquid-liquid phase separation (LLPS) aggregation. Inherited prion diseases humans neurodegeneration transgenic mice linked to expression anchorless (PrP), suggesting C-terminal glycosylphosphatidylinositol (GPI) PrP impedes spontaneous formation neurotoxic infectious species. Combining unique vitro vivo approaches, demonstrate anchoring membranes prevents LLPS PrP. Upon release from membrane, undergoes conformational transition detergent-insoluble aggregates. Our study demonstrates an essential role GPI preventing

Language: Английский

Protein quality control machinery: regulators of condensate architecture and functionality DOI

Anitha Rajendran,

Carlos A. Castañeda

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

2
Autophagy preferentially degrades non-fibrillar polyQ aggregates DOI Creative Commons
Dorothy Yanling Zhao, Felix J.B. Bäuerlein, Itika Saha

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(10), P. 1980 - 1994.e8

Published: May 1, 2024

Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark a group dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), protein HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but efficiency aggrephagy limited. Here, we used cryo-electron tomography visualize interactions autophagosomes with aggregates in cultured cells situ. We found that an amorphous aggregate exists next radially organized fibrils. Autophagosomes preferentially engulfed this material, mediated between autophagy receptor p62/SQSTM1 and non-fibrillar surface. In contrast, amyloid excluded p62 evaded clearance, resulting trapping autophagic structures. These results suggest limited clearing due inability interact productively non-deformable, fibrillar aggregates.

Language: Английский

Citations

11
NEMO Family of Proteins as Polyubiquitin Receptors: Illustrating Non-Degradative Polyubiquitination’s Roles in Health and Disease DOI Creative Commons
Chuan-Jin Wu

Cells, Journal Year: 2025, Volume and Issue: 14(4), P. 304 - 304

Published: Feb. 18, 2025

The IκB kinase (IKK) complex plays a central role in many signaling pathways that activate NF-κB, which turns on battery of genes important for immune response, inflammation, and cancer development. Ubiquitination is one the most prevalent post-translational modifications proteins best known targeting substrates proteasomal degradation. investigations NF-κB pathway primed unveiling non-degradative roles protein ubiquitination. NF-κB-essential modulator (NEMO) IKK regulatory subunit essential activation by diverse intrinsic extrinsic stimuli. studies centered NEMO as polyubiquitin-binding have remarkably advanced understandings how transmits signals to laid foundation determining molecular events demonstrating ubiquitination major driving element activation. Furthermore, these largely solved enigma can be activated employ distinct sets intermediaries transmitting signals. NEMO-related include optineurin, ABIN1, ABIN2, ABIN3, CEP55, ubiquitin chain receptors, play key sensing embodied different topologies polyubiquitin chains variety cellular processes body responses. Studies multifaceted promoted understanding about functions intracellular signaling, trafficking, proteostasis, DNA damage cell cycle control. In this review, I will also discuss dysfunction family protein-mediated associated with various diseases, including disorders, neurodegenerative cancer, microbial virulence factors target induce pathogenesis or manipulate host response. A profound bases valuable developing tailored approaches therapeutic purposes.

Language: Английский

Citations

0
Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice DOI Open Access
Karthikeyan Tangavelou, Shanya Jiang,

Somayeh Dadras

et al.

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

Published: March 13, 2025

Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, is released into the extracellular space. Microglia are first responders to tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis activate innate immune response gene expression nuclear factor-kappa B (NF-κB). However, longitudinal NF-κB activation in tauopathies whether pathological (pTau) contributes activity unknown. Here, we oligomers human Alzheimer's disease brain (AD-TO) mouse microglia macrophages reducing IκBα via promoting its secretion peaks at 9- 11-months age PS19Luc + hTauLuc mice, respectively. Reducing pTau pharmacological (DOX), genetic ( Mapt -/- ) or antibody-mediated neutralization (immunization with pT181-Qβ vaccine) reduces activity, together suggest driver of chronic neuroinflammation tauopathies. Neuronal activates microglial constitutively secreting inhibitor IκBα. mice age, Neutralizing vaccine (targeting threonine 181 tau) alleviates tauopathy mice.

Language: Английский

Citations

0
OTULIN orchestrates NCOA4-FTH1 complex to alleviate APAP-induced hepatocyte Ferroptosis DOI
Liyuan Gao, Xiaoyan Chang,

Yi Han

et al.

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 154, P. 114490 - 114490

Published: March 31, 2025

Language: Английский

Citations

0
Nucleocytoplasmic Hdac Inhibition Drives Acetylation-Dependent Tdp43 Mislocalization and Disulfide-Linked Aggregation DOI

Sungsu Lim,

Nataliia Lukianenko,

Aybuke Bekci

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Host–Pathogen Interaction Interface: Promising Candidate Targets for Vaccine-Induced Protective and Memory Immune Responses DOI Creative Commons
Gloria Guillermina Guerrero Manríquez, Vicente Madrid‐Marina, Aurora Martínez-Romero

et al.

Vaccines, Journal Year: 2025, Volume and Issue: 13(4), P. 418 - 418

Published: April 16, 2025

Vaccine formulations are a successful strategy against pathogen transmission because vaccine candidates induce effective and long-lasting memory immune responses (B CD4+ T cells) at systemic mucosal sites. Extracellular vesicles of lipoproteins, bioactive compounds from plants invertebrates (sponges) encapsulated in liposomes, glycoproteins can target these The developed mimic microbial pathogens way that successfully links the innate adaptive responses. In addition, vaccines plus adjuvants promote maintain an inflammatory response. this review, we aimed to identify host–pathogen interface as rich source candidate targets for vaccine-induced protective

Language: Английский

Citations

0
The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons DOI
Karthikeyan Tangavelou,

Virginie Bondu,

Mingqi Li

et al.

Published: April 15, 2025

Abstract The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimer’s disease (AD) related tauopathies causing aggregation. Protein ubiquitination with linkage specificity determines fate proteins that can be either degradative or stabilization signals. While linear M1-linked on protein aggregates a signaling hub recruits various ubiquitin-binding for coordinated actions turnover inflammatory NF-kB activation, deubiquitinase OTULIN counteracts ubiquitin signaling. However, exact role aggregate clearance AD unknown. Based our bulk RNA sequence analysis, human inducible pluripotent stem cell (iPSC)-derived neurons (iPSNs) from an individual late-onset sporadic (sAD2.1) show downregulation ligase activating factors (MAGEA2B MAGEA) long non-coding (lncRNA-OTULIN) compared to healthy control WTC11 iPSNs. In sAD2.1 iPSNs, downregulated lncRNA-OTULIN inversely correlated increased levels phosphorylated at p-S202/p-T205 (AT8), p-T231 (AT180), p-S396/p-S404 (PHF-1). Loss function using pharmacological inhibitor UC495 CRISPR-Cas9-mediated gene knockout causes significant reduction total AT8 epitope Whereas SH-SY5Y neuroblastoma cells, treating compound knocking out both mRNA consequently decreases AT8, AT180, PHF-1 epitopes. An additional analysis OUTLIN shows 14-fold down-regulation differential expression many other genes associated UPS, pathway, metabolism. Together, results suggest first time non-canonical regulating metabolism, may have pathogenic tauopathies.

Language: Английский

Citations

0
Secondary interactions in ubiquitin-binding domains achieve linkage or substrate specificity DOI Creative Commons

Martin A. Michel,

Simon R. Scutts, David Komander

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114545 - 114545

Published: July 23, 2024

Language: Английский

Citations

2
A conserved core region of the scaffold NEMO is essential for signal-induced conformational change and liquid-liquid phase separation DOI Creative Commons
Christopher J. DiRusso,

Anthony DeMaria,

Judy Wong

et al.

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(12), P. 105396 - 105396

Published: Oct. 27, 2023

Scaffold proteins help mediate interactions between protein partners, often to optimize intracellular signaling. Herein, we use comparative, biochemical, biophysical, molecular, and cellular approaches investigate how the scaffold NEMO contributes signaling in NF-κB pathway. Comparison of related optineurin from a variety evolutionarily distant organisms revealed that central region NEMO, called Intervening Domain (IVD), is conserved optineurin. Previous studies have shown this core IVD required for cytokine-induced activation IκB kinase (IKK). We show analogous can functionally replace IVD. also an intact formation disulfide-bonded dimers NEMO. Moreover, inactivating mutations abrogate ability form ubiquitin-induced liquid-liquid phase separation droplets vitro signal-induced puncta vivo. Thermal chemical denaturation truncated variants indicate IVD, while not intrinsically destabilizing, reduce stability surrounding regions due conflicting structural demands imparted on by flanking upstream downstream domains. This conformational strain mediates allosteric communication N- C-terminal Overall, these results support model which participates IKK/NF-κB pathway acting as mediator changes

Language: Английский

Citations

4