Structural basis for GSDMB pore formation and its targeting by IpaH7.8

Nature, Год журнала: 2023, Номер 616(7957), С. 590 - 597

Опубликована: Март 29, 2023

Abstract Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis 1,2 . Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on pyroptotic potential 3–7 Recently, was shown exhibit direct bactericidal activity 4 Shigella , an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated by secreting IpaH7.8, virulence effector triggers ubiquitination-dependent proteasomal degradation Here, we report the cryogenic electron microscopy structures human complex with IpaH7.8 pore. The structure GSDMB–IpaH7.8 identifies motif three negatively charged residues as structural determinant recognized IpaH7.8. Human, but not mouse, GSDMD contains conserved motif, explaining species specificity pore shows alternative splicing-regulated interdomain linker regulator formation. isoforms canonical normal whereas other attenuated or no activity. Overall, work sheds light molecular mechanisms recognition targeting GSDMs for

Язык: Английский

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Control of Cell Death in Health and Disease

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2023, Номер 19(1), С. 157 - 180

Опубликована: Окт. 3, 2023

Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, self-reactive cells. Apoptosis fragments cells in a manner limits immune activation, whereas the lytic programs of necroptosis release proinflammatory intracellular contents. fine-tunes tissue architecture during mammalian development, promotes homeostasis, is crucial for averting cancer autoimmunity. All three deployed to thwart spread pathogens. Disabling regulators signaling mice has revealed how excessive can fuel acute or chronic inflammation. Here we review strategies modulating context disease. For example, BCL-2 inhibitor venetoclax, an inducer apoptosis, approved treatment certain hematologic malignancies. By contrast, inhibition RIPK1, NLRP3, GSDMD, NINJ1 limit and/or large molecules from dying may benefit patients with inflammatory diseases.

Язык: Английский

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Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells

Cell Death and Differentiation, Год журнала: 2023, Номер 30(5), С. 1366 - 1381

Опубликована: Март 11, 2023

Abstract Gasdermin (GSDM)-mediated pyroptosis is functionally involved in multiple diseases, but Gasdermin-B (GSDMB) exhibit cell death-dependent and independent activities several pathologies including cancer. When the GSDMB pore-forming N-terminal domain released by Granzyme-A cleavage, it provokes cancer death, uncleaved promotes pro-tumoral effects (invasion, metastasis, drug resistance). To uncover mechanisms of pyroptosis, here we determined regions essential for death described first time a differential role four translated isoforms ( GSDMB1-4 , that differ alternative usage exons 6-7) this process. Accordingly, prove exon 6 translation mediated therefore, lacking GSDMB1-2 ) cannot provoke death. Consistently, breast carcinomas expression GSDMB2 not 6-containing variants GSDMB3-4 ), associates with unfavourable clinical-pathological parameters. Mechanistically, show constructs containing exon-6 membrane lysis concomitant mitochondrial damage. Moreover, have identified specific residues within other are important GSDMB-triggered as well impairment. Additionally, demonstrated cleavage proteases (Granzyme-A, Neutrophil Elastase caspases) different on regulation. Thus, immunocyte-derived can cleave all isoforms, only those 6, processing results induction. By contrast, or caspases produces short fragments no cytotoxic activity, thus suggesting these act inhibitory pyroptosis. Summarizing, our implications understanding complex roles future design GSDMB-targeted therapies.

Язык: Английский

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Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Immunological Reviews, Год журнала: 2023, Номер 314(1), С. 229 - 249

Опубликована: Янв. 19, 2023

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation plasma membrane (PM) macropores composed gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles gasdermin D (GSDMD) pyroptosis IL-1β release during inflammasome signaling have been extensively characterized macrophages. This involves cleavage GSDMD caspase-1 generate mediate efflux progression pyroptotic lysis. Neutrophils, which rapidly accumulate large numbers at sites damage, become the predominant local source coordination with their potent microbiocidal capacity. Similar macrophages, neutrophils express utilize same spectrum diverse platforms caspase-1-mediated GSDMD. Distinct from possess remarkable capacity resist GSDMD-dependent lysis preserve viability efficient killing while maintaining mechanisms export bioactive IL-1β. Rather, employ cell-specific conditionally engage GSDMD-mediated response bacterial pathogens use as niches. also mechanistically linked induction NETosis, signature neutrophil pathway expels decondensed nuclear DNA into extracellular compartments immobilization pathogens. review summarizes growing number recent studies produced new insights, unexpected mechanistic nuances, some controversies regarding regulation of, for, inflammasomes, pyroptosis, GSDMs immune responses.

Язык: Английский

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Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 4, 2023

Abstract The multifunctional GSDMB protein is an important molecule in human immunity. pyroptotic and bactericidal activity of a host response to infection by the bacterial pathogen Shigella flexneri , which employs virulence effector IpaH7.8 ubiquitinate target for proteasome-dependent degradation. Furthermore, selectively targets but not mouse GSDMD, suggesting non-canonical mechanism substrate selection. Here, we report crystal structure complex with IpaH7.8. Together biochemical functional studies, identify potential membrane engagement sites GSDMB, revealing general unique features gasdermin proteins recognition. We further illuminate how interacts delineate ubiquitinates suppresses GSDMB. Notably, guided our structural model, demonstrate that two residues α1-α2 loop make GSDMD invulnerable IpaH7.8-mediated These findings provide insights into versatile functions could open new avenues therapeutic interventions diseases, including cancers infections.

Язык: Английский

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Anti‐PD‐1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2‐Positive Gastric Cancer through Gasdermin B‐Cleavage Induced Pyroptosis

Advanced Science, Год журнала: 2023, Номер 10(30)

Опубликована: Авг. 16, 2023

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation immune checkpoints plays an essential role. Herein, a recombinant fully IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed its antitumor efficacy as well the underlying mechanism investigated. crosslinks physical interaction between Her2-positive tumor cells PD-1-positive T cells, resulting in significantly enhanced effects compared each parent or their combination, vitro vivo mouse models reconstituted using patient-derived xenografts organoids. Moreover, treatment also induces recruitment activation tumors. Mechanistically, triggers gasdermin B (GSDMB)-mediated pyroptosis leading recruiments cells. activated secret IFNγ, enhancing GSDMB expression establishing positive feedback loop cell killing. Notably, found be elevated providing rationale for IBI315's efficacy. supported here promising antibody-based immunotherapy approach preclinical studies, broadening therapeutic landscape this patient population.

Язык: Английский

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Gasdermins: a dual role in pyroptosis and tumor immunity

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Янв. 18, 2024

The gasdermin (GSDM) protein family plays a pivotal role in pyroptosis, process critical to the body’s immune response, particularly combatting bacterial infections, impeding tumor invasion, and contributing pathogenesis of various inflammatory diseases. These proteins are adept at activating inflammasome signaling pathways, recruiting effector cells, creating an microenvironment, initiating pyroptosis. This article serves as introduction GSDM protein-mediated pyroptosis providing overview GSDMs’ involvement immunity. Additionally, we explore potential applications GSDMs both innovative established antitumor strategies.

Язык: Английский

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Roles of pyroptosis in atherosclerosis pathogenesis

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 166, С. 115369 - 115369

Опубликована: Авг. 27, 2023

Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin protein-mediated membrane pore formation, swelling, and rapid lysis. Recent studies have suggested that pyroptosis closely related to atherosclerosis (AS). Previous reported involving endothelial cells (ECs), macrophages, smooth muscle (SMCs) plays an important role in the formation development AS. not only causes local inflammation but also amplifies inflammatory response it aggravates plaque instability, leading rupture thrombosis, eventually resulting acute cardiovascular events. In this review, we clarified some novel pathways mechanics presented potential drugs.

Язык: Английский

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The Asthma Risk Gene, GSDMB, Promotes Mitochondrial DNA-induced ISGs Expression

Deleted Journal, Год журнала: 2024, Номер 1(1), С. 10005 - 10005

Опубликована: Янв. 1, 2024

Released mitochondrial DNA (mtDNA) in cells activates cGAS-STING pathway, which induces expression of interferon-stimulated genes (ISGs) and thereby promotes inflammation, as frequently seen asthmatic airways. However, whether the genetic determinant, Gasdermin B (GSDMB), most replicated asthma risk gene, regulates this pathway remains unknown. We set out to determine how GSDMB mtDNA-activated subsequent ISGs induction human airway epithelial cells. Using qPCR, ELISA, native polyacrylamide gel electrophoresis, co-immunoprecipitation immunofluorescence assays, we evaluated regulation on both BEAS-2B primary normal bronchial (nHBEs). mtDNA was extracted plasma samples from asthmatics correlation between levels eosinophil counts analyzed. is significantly associated with RANTES nasal brushing Genes-environments Admixture Latino Americans (GALA) II study. Over-expression DNA-induced IFN nHBEs. Conversely, knockout led weakened interferon (IFNs) Mechanistically, interacts C-terminus STING, promoting translocalization STING Golgi, leading phosphorylation IRF3 IFNs ISGs. copy number serum correlated blood especially male subjects. activation poly (dA:dT)-induced cells, enhanced

Язык: Английский

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Pyroptosis in spinal cord injury

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Ноя. 17, 2022

Spinal cord injury (SCI) often brings devastating consequences to patients and their families. Pathophysiologically, the primary insult causes irreversible damage neurons glial cells initiates secondary cascade, further leading inflammation, ischemia, death. In SCI, release of various inflammatory mediators aggravates nerve injury. Pyroptosis is a new pro-inflammatory pattern regulated cell death (RCD), mainly mediated by caspase-1 or caspase-11/4/5. Gasdermins family are pore-forming proteins known as executor pyroptosis gasdermin D (GSDMD) best characterized. occurs in multiple central nervous system (CNS) types, especially plays vital role development SCI. We review here evidence for focus on different crosstalk between them. addition, we discuss interaction other forms RCD also summarize therapeutic strategies inhibition, so provide novel ideas improving outcomes following

Язык: Английский

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