The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(4), P. 2071 - 2096

Published: April 2, 2024

Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor which use the ER-SURF pathway employ surface of endoplasmic reticulum (ER) as an important sorting platform. How they reach import machinery from ER is not known. Here we show that contact sites play crucial role ER-to-mitochondria transfer proteins. The encounter structure (ERMES) Tom70, together with Djp1 Lam6, part two parallel partially redundant delivery routes. When prevented by loss these sites, many precursors inner membrane left stranded membrane, resulting dysfunction. Our observations support active protein biogenesis.

Language: Английский

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Mitochondrial protein import stress

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

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Induction of the Inflammasome by the SARS‐CoV‐2 Accessory Protein ORF9b, Abrogated by Small‐Molecule ORF9b Homodimerization Inhibitors

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(2)

Published: Feb. 1, 2025

ABSTRACT Viral accessory proteins play critical roles in viral escape from host innate immune responses and inflammatory pathogenesis. Here we show that the SARS‐CoV‐2 protein, ORF9b, but not other (ORF3a, ORF3b, ORF6, ORF7, ORF8, ORF9c, ORF10), strongly activates inflammasome‐dependent caspase‐1 A549 lung carcinoma cells THP‐1 monocyte‐macrophage cells. Exposure to lipopolysaccharide (LPS) ATP additively enhanced activation of by suggesting ORF9b LPS follow parallel pathways inflammasome caspase‐1. Following rational silico approaches, have designed small molecules capable inhibiting homodimerization which experimentally inhibited ORF9b‐ORF9b homotypic interactions, caused mitochondrial eviction ORF9b‐induced cells, cytokine release restored type I interferon (IFN‐I) signaling suppressed both cell models. These are first‐in‐class compounds targeting a protein for viral‐induced exacerbated inflammation responses, with potential mitigating severe immunopathogenic damage induced highly pathogenic coronaviruses restoring antiviral curtailed infection.

Language: Английский

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A Comparison of Conserved Features in the Human Coronavirus Family Shows That Studies of Viruses Less Pathogenic than SARS-CoV-2, Such as HCoV-OC43, Are Good Model Systems for Elucidating Basic Mechanisms of Infection and Replication in Standard Laboratories

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 256 - 256

Published: Feb. 13, 2025

In 2021, at the height of COVID-19 pandemic, coronavirus research spiked, with over 83,000 original articles related to word "coronavirus" added online resource PubMed. Just 2 years later, in 2023, only 30,900 were added. While, irrefutably, funding drastically decreased, a possible explanation for decrease interest is that projects on SARS-CoV-2, causative agent COVID-19, halted due challenge establishing good cellular or animal model system. Most laboratories do not have capabilities culture SARS-CoV-2 'in house' as this requires Biosafety Level (BSL) 3 laboratory. Until recently, BSL laboratory endemic coronaviruses was arduous low cytopathic effect isolated cell infection models and lack means quantify viral loads. The purpose review article compare human provide an assessment latest techniques use coronaviruses-HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1-as lower-biosafety-risk more pathogenic coronaviruses-SARS-CoV-2, SARS-CoV, MERS-CoV.

Language: Английский

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Protein insertion into the inner membrane of mitochondria: routes and mechanisms

FEBS Open Bio, Journal Year: 2024, Volume and Issue: 14(10), P. 1627 - 1639

Published: April 25, 2024

The inner membrane of mitochondria contains hundreds different integral proteins. These proteins transport molecules into and out the matrix, they carry multifold catalytic reactions promote biogenesis or degradation mitochondrial constituents. Most are encoded by nuclear genes synthesized in cytosol from where imported translocases outer membrane. Three import routes direct allow them to acquire their appropriate topology. First, intermediates can be arrested at level TIM23 translocase a stop-transfer sequence reach lateral insertion. Second, fully translocated through complex matrix insert an export-like reaction. Carriers other polytopic embark on third insertion pathway: these hydrophobic employ specialized TIM22 intermembrane space (IMS) This review article describes three targeting provides overview machinery that promotes topogenesis

Language: Английский

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Betacoronavirus internal protein: role in immune evasion and viral pathogenesis

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

ABSTRACT Betacoronaviruses express a small internal (I) protein that is encoded by the same subgenomic RNA (sgRNA) as nucleocapsid (N) protein. Translation of +1 reading frame N sgRNA through leaky ribosomal scanning leads to expression I The an accessory reported evade host innate immune responses during coronavirus infection. Previous studies have shown proteins severe acute respiratory syndrome (SARS-CoV), SARS-CoV-2, and Middle East suppress type interferon production distinct mechanisms. In this review, we summarize current knowledge on betacoronaviruses from different subgenera, with emphasis its function role in pathogenesis.

Language: Английский

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MitoStores: stress-induced aggregation of mitochondrial proteins

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

Published: Jan. 20, 2025

Abstract Most mitochondrial proteins are synthesized in the cytosol and post-translationally imported into mitochondria. If rate of protein synthesis exceeds capacity import machinery, precursor can transiently accumulate cytosol. The cytosolic accumulation precursors jeopardizes cellular homeostasis (proteostasis) be cause diseases. In order to prevent these toxic effects, most non-imported rapidly degraded by ubiquitin-proteasome system. However, cells employ a second layer defense which is facilitated sequestration transient aggregates. formation such structures triggered nucleation factors as small heat shock proteins. Disaggregases chaperones liberate from aggregates pass them on machinery or, under persistent stress conditions, proteasome for degradation. Owing their role buffering systems, were referred MitoStores. This review articles provides general overview about MitoStore concept early stages biogenesis yeast and, cases where aspects differ, mammalian cells.

Language: Английский

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Dissecting the COVID‐19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARS‐CoV‐2 Structural Proteins

Journal of Molecular Recognition, Journal Year: 2025, Volume and Issue: 38(2)

Published: Feb. 5, 2025

ABSTRACT Severe acute respiratory syndrome coronavirus (SARS‐CoV), the virus responsible for COVID‐19, interacts with host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining disease's severity host's ability to clear virus. Given virus's substantial socioeconomic impact, high morbidity mortality rates, public health importance, understanding these is essential. This article examines diverse responses triggered by SARS‐CoV‐2's structural proteins, including spike (S), membrane (M), envelope (E), nucleocapsid (N) along nonstructural proteins (NSPs) open reading frames. play pivotal roles modulation, facilitating viral replication, evading detection, contributing severe inflammatory such as cytokine storms distress (ARDS). The employs strategies like suppressing type I interferon production disrupting key antiviral pathways, MAVS, OAS‐RNase‐L, PKR. study also explores pathways govern activation suppression of throughout COVID‐19. By analyzing sensing receptors initiated upon recognizing SARS‐CoV‐2 this review elucidates associated response Understanding offers valuable insights therapeutic interventions informs strategies, a deeper COVID‐19 immunopathogenesis.

Language: Английский

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Silver Nanoparticle‐Mediated Antiviral Efficacy against Enveloped Viruses: A Comprehensive Review

Global Challenges, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Abstract Viral infections continue to pose a significant challenge global health, with increasing resistance conventional antiviral therapies highlighting the urgent need for alternative treatment strategies. Silver nanoparticles (AgNPs) have attracted attention as broad‐spectrum agents due their unique physicochemical properties and ability target multiple stages of viral infection. This review provides comprehensive analysis mechanisms AgNPs, efficacy against clinically relevant enveloped viruses such influenza, herpes simplex, hepatitis B, coronaviruses. How key nanoparticle characteristics, including size, shape, surface functionalization, synthesis methods, influence performance is examined. Studies indicate that AgNPs exert effects through direct interactions particles, inhibition adhesion, entry into host cells disruption replication. Furthermore, potential applications in therapeutic formulations, coatings, nanomedicine‐based strategies are explored. Despite promise, challenges regarding cytotoxicity, stability, large‐scale production must be addressed ensure safe effective clinical use. highlights transformative therapy further investigation facilitate translation fight emerging drug‐resistant infections.

Language: Английский

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TIMM10 enhances MAVS mediated innate immune response against influenza A virus infection

Colloids and Surfaces A Physicochemical and Engineering Aspects, Journal Year: 2025, Volume and Issue: unknown, P. 136900 - 136900

Published: April 1, 2025

Language: Английский

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