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1.
Nature ; 616(7957): 590-597, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36991122

RESUMO

Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis1,2. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential3-7. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity4. Shigella, an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated host defence by secreting IpaH7.8, a virulence effector that triggers ubiquitination-dependent proteasomal degradation of GSDMB4. Here, we report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore. The structure of the GSDMB-IpaH7.8 complex identifies a motif of three negatively charged residues in GSDMB as the structural determinant recognized by IpaH7.8. Human, but not mouse, GSDMD contains this conserved motif, explaining the species specificity of IpaH7.8. The GSDMB pore structure shows the alternative splicing-regulated interdomain linker in GSDMB as a regulator of GSDMB pore formation. GSDMB isoforms with a canonical interdomain linker exhibit normal pyroptotic activity whereas other isoforms exhibit attenuated or no pyroptotic activity. Overall, this work sheds light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and shows a structural determinant in GSDMB critical for its pyroptotic activity.


Assuntos
Proteínas de Bactérias , Gasderminas , Proteínas Citotóxicas Formadoras de Poros , Animais , Humanos , Camundongos , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/ultraestrutura , Sítios de Ligação , Sequência Conservada , Microscopia Crioeletrônica , Proteínas Citotóxicas Formadoras de Poros/química , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Proteínas Citotóxicas Formadoras de Poros/ultraestrutura , Domínios Proteicos , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/ultraestrutura , Piroptose , Shigella , Especificidade da Espécie , Gasderminas/química , Gasderminas/metabolismo , Gasderminas/ultraestrutura
2.
Immunol Rev ; 297(1): 83-95, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32713036

RESUMO

Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline-encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor-dependent type I IFN synthesis followed by JAK/STAT-dependent interferon-stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase-1. Caspase-1 cleaves and activates the pro-inflammatory cytokines such as IL-1ß and IL-18 and a pore-forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome-dependent and inflammasome-independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.


Assuntos
Proteínas de Ligação a DNA , Inflamassomos , Caspase 1 , Interleucina-18 , Piroptose
3.
Sci Rep ; 8(1): 15501, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341337

RESUMO

Pathogenic Salmonella species initiate infection by invading non-phagocytic intestinal epithelial cells (IEC). This invasion is brought about by a number of Salmonella invasion promoting molecules (Sips) encoded by the Salmonella Pathogenicity Island - 1 (SPI-1). Intracellular delivery of some of these molecules also brings about caspase-1 - mediated pyroptotic cell death that contributes to pathogen clearance. These molecules are secreted and delivered inside cells upon contact of Salmonella with one or more host signals whose identity has not been established. We show that lysophosphatidylcholine (LPC) released following activation of caspase-1 in Salmonella - infected cells and abundant in plasma amplifies production of Sips from this pathogen and promotes its cellular invasion. LPC brings about adenylate cyclase and cAMP receptor protein (CRP) - dependent de novo synthesis of SipC that is accompanied by its translocation to bacterial cell surface and release into the outside milieu. Treatment of Salmonella with LPC produces sustained induction of SPI - 1 transcriptional regulator, hilA. Our findings reveal a novel host lipid sensing - driven regulatory mechanism for Salmonella invasion.


Assuntos
Enterócitos/microbiologia , Interações Hospedeiro-Patógeno , Lipídeos/química , Salmonella typhimurium/patogenicidade , Animais , Proteínas de Bactérias/metabolismo , Caspase 1/metabolismo , Morte Celular , AMP Cíclico/metabolismo , Proteína Receptora de AMP Cíclico/metabolismo , Células HeLa , Humanos , Lipídeos/sangue , Lisofosfolipídeos/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais
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