Interferon- γ and infectious diseases: Lessons and prospects

Science, Год журнала: 2024, Номер 384(6693)

Опубликована: Апрель 18, 2024

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these would benefit not just new medicines vaccines but also a better understanding what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-γ (IFN-γ), protein secreted by lymphocytes. Forty years ago, IFN-γ was identified as macrophage-activating factor, and, in recent years, there has been resurgent interest biology its role human defense. Here we assess current IFN-γ, revisit designation an "interferon," weigh prospects therapeutic globally pervasive microbial pathogens.

Язык: Английский

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Inducible antibacterial responses in macrophages

Nature reviews. Immunology, Год журнала: 2024, Номер 25(2), С. 92 - 107

Опубликована: Сен. 18, 2024

Язык: Английский

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Honeysuckle‐Derived Carbon Dots With Robust Catalytic and Pharmacological Activities for Mitigating Lung Inflammation by Inhibition of Caspase11/GSDMD‐Dependent Pyroptosis

Advanced Functional Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Abstract The catalytic activity of carbon dots (CDs) has generated significant interest regarding their potential applications within the biomedical field. However, structure‐activity relationship CDs and pharmacological mechanisms in disease treatment have yet to be comprehensively elucidated. In this study, two distinct types exhibiting superoxide dismutase (SOD)‐like enzymatic activities are synthesized through hydrothermal (Hy‐CDs) carbonization (Ca‐CDs) methods, utilizing Honeysuckle as common material precursor. Through comparative analysis, surface group modifications, theoretical calculations, it is determined that SOD‐like primarily originated from stabilizing influence amino on (•O 2 − ) intermediate its conjugation π‐system, facilitating electron transfer. vitro experiments demonstrated Hy‐CDs effectively alleviated cellular oxidative stress inhibited secretion pro‐inflammatory cytokines. Furthermore, bioactivity properties contribute pronounced therapeutic efficacy acute lung injury (ALI) ischemia/reperfusion (LIRI). Guided by transcriptomic analysis Western blotting, inhibit Caspase11/GSDMD‐dependent non‐classical pyroptosis down‐regulating GBP2 protein expression, thereby contributing inflammation. This study elucidates underlying biological applications.

Язык: Английский

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PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection

Science, Год журнала: 2023, Номер 382(6666)

Опубликована: Окт. 6, 2023

Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense attacking intracellular pathogens and inducing programmed cell death. Working in human macrophages, we discovered that GBP1 expression absence IFN-γ killed cells induced Golgi fragmentation. exposure improved macrophage survival through activity kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration 14-3-3σ, which thereby prevented membrane association. During

Язык: Английский

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Structural basis of antimicrobial membrane coat assembly by human GBP1

Nature Structural & Molecular Biology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 11, 2024

Abstract Guanylate-binding proteins (GBPs) are interferon-inducible guanosine triphosphate hydrolases (GTPases) mediating host defense against intracellular pathogens. Their antimicrobial activity hinges on their ability to self-associate and coat pathogen-associated compartments or cytosolic bacteria. Coat formation depends GTPase but how nucleotide binding hydrolysis prime remains unclear. Here, we report the cryo-electron microscopy structure of full-length human GBP1 dimer in its guanine nucleotide-bound state describe molecular ultrastructure liposomes bacterial lipopolysaccharide membranes. Conformational changes middle effector domains expose isoprenylated C terminus for membrane association. The α-helical form a parallel, crossover arrangement essential position extended domain intercalation into layer gram-negative Nucleotide create oligomeric scaffolds with contractile abilities that promote extrusion fragmentation. Our data offer structural mechanistic framework understanding functions immunity.

Язык: Английский

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Template matching and machine learning for cryo-electron tomography

Current Opinion in Structural Biology, Год журнала: 2025, Номер 93, С. 103058 - 103058

Опубликована: Май 14, 2025

Cryo-electron tomography is the best-suited imaging technique for visual proteomics. Recent advances have increased number, quality, and resolution of tomograms. However, object detection bottleneck task analysis workflow because, so far, only a few molecules can be detected by computer methods pattern recognition. This article introduces major challenges in detecting molecular complexes cryo-electron tomography. paper also identifies limitations current methods. Finally, it describes approaches proposed to overcome these limitations.

Язык: Английский

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GBP1 promotes acute rejection after liver transplantation by inducing Kupffer cells pyroptosis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2024, Номер 1871(3), С. 167644 - 167644

Опубликована: Дек. 27, 2024

Язык: Английский

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Genomic and functional adaptations in guanylate-binding protein 5 (GBP5) highlight specificities of bat antiviral innate immunity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

Bats are asymptomatic reservoirs of several zoonotic viruses. This may result from long-term coevolution between viruses and bats, that have led to host adaptations contributing an effective balance strong antiviral responses with innate immune tolerance. To better understand these virus-host interactions, we combined comparative transcriptomics, phylogenomics functional assays characterize the evolution bat factors. First, stimulated type I interferon pathway in Myotis yumanensis primary cells identified guanylate-binding protein 5 (GBP5) as most differentially expressed interferon-stimulated gene (ISG). Phylogenomic analyses showed GBP5 has been under episodic positive selection, numerous rapidly evolving sites species-specific duplications, suggesting past evolutionary arms races. Functional tests on orthologs ten species covering >60 million years Chiroptera revealed species- virus-specific restrictions against RNA (retrovirus HIV, rhabdoviruses European lyssavirus VSV), which typical signatures viral epidemics. Interestingly, also observed a lineage-specific loss prenylation motif common ancestor Pipistrellus Eptesicus associated different subcellular localization functions. Resurrection ancestral fuscus rescued its localization, but not complete activities, additional determinants necessary for restriction. Altogether, our results highlight contribute specific immunity provide insights into effector GBP5. is upon stimulation cells. Bat evolved genomic genetic diversification, including early stop codon leading truncation motif.GBP5 diversification bats impacts their functions.Bat GBP5s exhibit virus-specificity ability inhibit infectivity particles, bearing glycoproteins retroviral vesicular stomatitis virus lyssavirus-1.Resurrection rescues full activity.

Язык: Английский

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SLICK: A Sandwich-LIke Culturing Kit for in situ Cryo-ET Sample Preparation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 16, 2025

In situ cryo-electron tomography (cryo-ET) has recently been widely used in observing subcellular structures and macromolecules their native states at high resolution. One of the reasons that it not more adopted by cell biologists structural is difficulties sample preparation. Here we present Sandwich-LIke Culturing Kit (SLICK), simplifying procedure increasing throughput for preparation cryo-ET (69 words).

Язык: Английский

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Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Фев. 22, 2025

Guanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens. GBP2 is one the two highly inducible GBPs, yet precise mechanisms underlying activation and regulation GBP2, in particular nucleotide-induced conformational changes remain poorly understood. In this study, we elucidate structural plasticity upon nucleotide binding through crystallographic analysis. By determining crystal structures G domain (GBP2GD) complex with GDP nucleotide-free full-length K51A mutation (GBP2K51A), unveil distinct states adopted by nucleotide-binding pocket distal regions protein. Comparison between GBP2K51A structure homologous reveals notable movement C-terminal helical region, along domain. Through comparative analysis, identify subtle but critical differences nucleotide-bound providing insights into molecular basis its dimer-monomer transition enzymatic activity. These findings pave way for future investigations aimed at elucidating GBP2's role immune response open avenues exploring how unique functions GBPs could be leveraged to combat pathogen invasion. Using biophysical studies, authors provide insight interferon-induced guanylate-binding protein 2. towards new therapeutic strategies overcome

Язык: Английский

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