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

Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris DOI Creative Commons
Peidian Shi, Wenjie Chen, Xinxing Lyu

et al.

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

Published: July 24, 2024

Abstract Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving cohort of 102 patients with sporadic 800 healthy controls Han Chinese population identify significant associations ( P = 1.73 × 10 −6 ) between heterozygous mutations in the Keratin 32 gene KRT32 ). found to be predominantly localized basal keratinocytes exhibits inhibitory effect on skin inflammation antagonizing NF-κB pathway. Mechanistically, binds NEMO, promoting excessive K48-linked polyubiquitination NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function among result hyperactivation. Importantly, Krt32 knockout mice exhibit PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function response external pro-inflammatory stimuli. This proposes role for regulating immune responses, damaging variants being important driver development. These findings offer insights into regulation homeostasis keratin open up possibility using as therapeutic target PRP.

Language: Английский

Citations

1
Regulated proteolysis induces aberrant phase transition of biomolecular condensates into aggregates; a protective role for the chaperone Clusterin DOI Creative Commons
Janine Kamps, Patricia Yuste‐Checa, Fatemeh Mamashli

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168839 - 168839

Published: Oct. 1, 2024

Language: Английский

Citations

1
The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer’s Disease DOI Open Access
Karthikeyan Tangavelou, Kiran Bhaskar

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12335 - 12335

Published: Nov. 17, 2024

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S macroautophagy, aggrephagy. Neurofibrillary tangles (NFTs) form upon impairment of aggrephagy, eventually, ubiquitin chaperone valosin-containing protein (VCP) heat shock 70 kDa (HSP70) are recruited sites NFTs for extraction ubiquitin-proteasome system (UPS)-mediated degradation. However, degradation in neurons allows be secreted into extracellular space. Secreted can monomers, oligomers, paired helical filaments (PHFs), which seeding competent pathological that endocytosed/phagocytosed healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes, often causing proteotoxic stress eventually triggers senescence. Senescent secrete senescence-associated secretory phenotype (SASP) factors, trigger cellular atrophy, decreased brain volume human AD. molecular mechanisms senescence not entirely understood an emerging area research. Therefore, this comprehensive review summarizes pertinent studies provided evidence sequential degradation, failure, mechanistic link between tau-driven

Language: Английский

Citations

1
Platelet-rich plasma combined with isometric quadriceps contraction regulates autophagy in chondrocytes via the PI3K/AKT/mTOR pathway to promote cartilage repair in knee osteoarthritis DOI Creative Commons
Liang Cheng, Shuwan Chang, Yajun Tan

et al.

Regenerative Therapy, Journal Year: 2024, Volume and Issue: 28, P. 81 - 89

Published: Dec. 4, 2024

Language: Английский

Citations

1
Biomolecular condensates: phasing in regulated host–pathogen interactions DOI
Kun Chen, Xuetao Cao

Trends in Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

Citations

1
Antibody-dependent Intracellular neutralisation by TRIM21 is potentiated by HOIP and linear ubiquitin chains DOI Creative Commons
Christopher Green, Konstanze F. Winklhofer, Adam J. Fletcher

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 3, 2024

Abstract Antibody-dependent intracellular neutralisation (ADIN) promotes the rapid proteasomal degradation of viruses and other large substrates in cytosol. It is dependent on detection virus-bound antibodies by Fc receptor E3 ligase TRIM21, followed disassembly virus unfoldase VCP/p97. not known how VCP recruited to TRIM21. We performed a limited siRNA knock-down screen adaptors determine their involvement ADIN. Knock-down HOIP, only ubiquitin capable generating linear chains, resulted impaired neutralisation. HOIPIN-8, HOIP inhibitor, showed concentration-dependent reduction found that activity ADIN its binding domains PUB domain which recruits VCP. OTULIN, deubiquitinating enzyme exclusively cleaves potentiated virus. Our results expand role chains proteostasis.

Language: Английский

Citations

0
Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: implications for prion diseases DOI Open Access
Kalpshree Gogte,

Simon Kriegler,

Verian Bader

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 9, 2024

ABSTRACT 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 restriction conformational degrees freedom by membrane anchor stabilizes native conformation suppresses liquid-liquid phase separation 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 novel vitro vivo approaches, anchoring membranes prevents PrP. Upon release from membrane, undergoes rapid transition detergent-insoluble aggregates. Our study supports an essential role GPI preventing C .

Language: Английский

Citations

0
DnaK of Parvimonas micra OMVs interacted with the host fibroblast Bag3-IKK-γ axis to accelerate TNF-α secretion in oral lichen planus DOI
Xiaoli Ji,

Mengfan Zhi,

Xiufeng Gu

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 15, 2024

Abstract Background Oral lichen planus (OLP) is one of the most frequent oral mucosal diseases associated with chronic inflammation despite extremely insufficient knowledge its pathogenic mechanism.Results Here, microbiome buccal and lip mucosae, tongue dorsum saliva among OLP patients healthy individuals was analyzed. It found that microbiome, especially mucosa, varied significantly in patients. Network, random forest Netshift analyses simultaneously showed Parvimonas micra (P. micra) an important bacterium disease. Fluorescence situ hybridization (FISH) single-cell ribonucleic acid (RNA) sequencing profiling suggested fibroblasts were candidate target characteristic up-regulating nuclear factor kappa-B (NF-қB) signaling pathway related to tumor necrosis factor-alpha (TNF-α) communicating multiple immune cell types. Mechanism analysis P. micra, micra-derived conditional medium (CM) outer membrane vesicles (OMVs) could induce activity NF-қB inhibit autophagy fibroblasts. As main effectors, DnaK OMVs promote TNF-α secretion via DnaK-Bcl-2 athanogene 3 (Bag3)-inhibitor kinase subunit gamma (IKK-γ) axis.Conclusions Here we demonstrate micra’s OMV drives -Bag3-IKK-γ/NF-қB axis as new insights into mechanism OLP.

Language: Английский

Citations

0
α-Synuclein ubiquitination – functions in proteostasis and development of Lewy bodies DOI Creative Commons
Hung-Hsiang Ho, Simon S. Wing

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Nov. 12, 2024

Synucleinopathies are neurodegenerative disorders characterized by the accumulation of α -synuclein containing Lewy bodies. Ubiquitination, a key post-translational modification, has been recognized as pivotal regulator -synuclein’s cellular dynamics, influencing its degradation, aggregation, and associated neurotoxicity. This review examines comprehensively current understanding ubiquitination role in pathogenesis synucleinopathies, particularly context Parkinson’s disease. We explore molecular mechanisms responsible for ubiquitination, with focus on roles E3 ligases deubiquitinases implicated degradation process which occurs primarily through endosomal lysosomal pathway. The further discusses how dysregulation these contributes to aggregation LB formation offers suggestions future investigations into ubiquitination. Understanding processes may shed light potential therapeutic avenues that can modulate alleviate pathological impact synucleinopathies.

Language: Английский

Citations

0
Alpha-synuclein Fibrils Inhibit Activation of the BDNF/ERK Signaling Loop in the mPFC to Induce Parkinson's Disease-like Alterations with Depression DOI Creative Commons
Zhuoran Ma,

Yan Xu,

Piaopiao Lian

et al.

Neuroscience Bulletin, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 28, 2024

Depression (Dep) is one of the most common concomitant symptoms Parkinson's disease (PD), but there a lack detailed pathologic evidence for occurrence PD-Dep. Currently, management from both conditions using conventional pharmacological interventions remains formidable task. In this study, we found impaired activation extracellular signal-related kinase (ERK), reduced levels transcription and translation, decreased expression brain-derived neurotrophic factor (BDNF) in medial prefrontal cortex (mPFC) PD-Dep rats. We demonstrated that abnormal phosphorylation α-synuclein (pS129) induced tropomyosin-related receptor type B (TrkB) retention at neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. chose SEW2871 as an ameliorator upregulate ERK phosphorylation. The results showed rats exhibited improvement behavioral manifestations PD depression. addition, reduction pS129 was accompanied by restoration function BDNF/ERK loop mPFC

Language: Английский

Citations

0