The gasdermin family: emerging therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Language: Английский

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Membrane atg8ylation in Canonical and Noncanonical Autophagy

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168532 - 168532

Published: March 12, 2024

Language: Английский

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Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010787 - e010787

Published: Feb. 1, 2025

Background Lung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value LUAD remains largely unexplored. Methods We developed a modification learning signature (PTMLS) using machine techniques, analyzing data from 1231 patients across seven global cohorts. The signature’s predicting immunotherapy response was evaluated 12 cohorts spanning multiple cancer types (n=1201). An in-house tissue cohort (n=171) used validate beta-1,4-galactosyltransferase 2’s (B4GALT2’s) significance. role of B4GALT2 immune exclusion investigated through vivo vitro experiments. Results established PTMLS exhibited exceptional predictive capabilities patient outcomes, surpassing the 98 existing indicators. system’s validated diverse malignancy categories for immunotherapeutic assessment. From biological perspective, correlations were observed between immunological parameters, whereby elevated levels characterized by attenuated responses immunologically cold neoplastic features. Within framework, identified as crucial molecular component (r=0.82, p<0.05), its heightened expression linked unfavorable clinical outcomes cases, particularly specimens exhibiting CD8-depleted phenotypes. spatial distribution patterns cell populations, specifically CD8+ T lymphocytes CD20+ B lymphocytes, elucidated multiplexed immunofluorescence analysis. Laboratory investigations subsequently B4GALT2’s regulatory on cellular expansion both laboratory cultures animal models. Significantly, suppression found enhance lymphocyte populations functional status, thereby potentiating anti-programmed death protein 1 studies. This phenomenon reduced CD62L+CD8 alongside GZMB+/CD44+/CD69+CD8 populations. Conclusion system represents an effective instrument individualized evaluation stratification identification previously unrecognized oncogenic factor involved novel therapeutic avenue optimization.

Language: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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A new dawn beyond lysine ubiquitination

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(8), P. 802 - 811

Published: July 27, 2022

Language: Английский

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The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(10)

Published: Oct. 23, 2023

Abstract The selenium-containing enzyme GPX4 moonlights as a central regulator of ferroptosis, an iron-dependent, nonapoptotic form regulated cell death caused by lipid peroxidation. Yet, little is known about the mechanisms underlying regulation its post-transcriptional modifications. Here, we identify tripartite motif-containing protein TRIM26 E3 ubiquitin ligase GPX4. directly interacts with through Ring domain and catalyzes ubiquitination at K107 K117, which promotes switch in polyubiquitination from K48 to K63, thus enhancing stability. Moreover, PLK1-mediated S127 phosphorylation enhances interaction between Inhibition causes reduction K63-linked diminishes levels tumor cells. Further investigation revealed that overexpressed glioma silencing dramatically impedes ferroptosis resistance tumorigenesis vivo vitro. Clinically, expression shows direct correlation PLK1 samples associated poor outcome patients glioma. Collectively, these findings define role suggest potential strategy for treatment.

Language: Английский

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Protein degradation: expanding the toolbox to restrain cancer drug resistance

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Jan. 24, 2023

Abstract Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib proteolysis-targeting chimeric have been developed. Compared intervention at the transcriptional level, targeting process seems be more rapid direct strategy. Proteasomal proteolysis lysosomal are most critical quality control systems responsible for proteins or organelles. Although proteasomal inhibitors (e.g., chloroquine) achieved certain improvements some application scenarios, their routine practice is still long way off, which due lack precise capabilities inevitable side effects. In-depth studies regulatory mechanism regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), chaperones, expected provide clues developing reducing Here, we discuss underlying mechanisms regulating efflux, metabolism, DNA repair, target alteration, downstream bypass signaling, sustaining stemness, tumor microenvironment remodeling delineate functional roles resistance. We also highlight specific DUBs, discussing possible modulating cancer A systematic summary molecular basis by regulates will help facilitate development appropriate strategies.

Language: Английский

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PROTACs: Novel tools for improving immunotherapy in cancer

Cancer Letters, Journal Year: 2023, Volume and Issue: 560, P. 216128 - 216128

Published: March 16, 2023

Language: Английский

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Advances in post-translational modifications of proteins and cancer immunotherapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 22, 2023

Protein post-translational modification (PTM) is a regulatory mechanism for protein activity modulation, localization, expression, and interactions with other cellular molecules. It involves the addition or removal of specific chemical groups on amino acid residues proteins. Its common forms include phosphorylation, ubiquitylation, methylation, acetylation. Emerging research has highlighted lactylation, succinylation, glycosylation. PTMs are involved in vital biological processes. The occurrence development diseases depends abundance regulated by various PTMs. In addition, advancements tumor immunotherapy have revealed that PTM also proliferation, activation, metabolic reprogramming immune cells microenvironment. These play an important role immunotherapy. this review, we comprehensively summarize several types This review could provide new insights future directions

Language: Английский

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TRIB3–TRIM8 complex drives NAFLD progression by regulating HNF4α stability

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 80(5), P. 778 - 791

Published: Jan. 21, 2024

Language: Английский

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