Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis DOI Creative Commons
Xinran Li, Wei Li, Cong Xiang

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114728 - 114728

Published: Sept. 1, 2024

Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage gasdermin proteins B-E (GSDMB-GSDME) well established as trigger pyroptosis, but the intracellular activation mechanism GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced GSDMA. Nutrient stresses stimulate via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation Ser353 on human ULK1 or phospho-mimetic Ser353Asp mutant liberates from auto-inhibition, facilitating its membrane targeting initiation pyroptosis. To further validate significance phosphorylation, generated constitutively active Ser354Asp mouse Gsdma, which induced skin inflammation hyperplasia in mice, reminiscent phenotypes with activated Gsdma. This study uncovers underlying cellular response to nutrient stress.

Language: Английский

The gasdermin family: emerging therapeutic targets in diseases DOI Creative Commons
Cheng‐long Zhu, Sheng Xu, Ruoyu Jiang

et al.

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

Citations

26
Gasdermins as evolutionarily conserved executors of inflammation and cell death DOI
Kaiwen W. Chen, Petr Brož

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(9), P. 1394 - 1406

Published: Aug. 26, 2024

Language: Английский

Citations

15
Mechanistic insights into gasdermin-mediated pyroptosis DOI
Yang Bai,

Youdong Pan,

Xing Liu

et al.

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

Published: March 24, 2025

Language: Английский

Citations

1
Harnessing Pyroptosis for Cancer Immunotherapy DOI Creative Commons
Christopher M. Bourne, Cornelius Y. Taabazuing

Cells, Journal Year: 2024, Volume and Issue: 13(4), P. 346 - 346

Published: Feb. 16, 2024

Cancer immunotherapy is a novel pillar of cancer treatment that harnesses the immune system to fight tumors and generally results in robust antitumor immunity. Although has achieved remarkable clinical success for some patients, many patients do not respond, underscoring need develop new strategies promote Pyroptosis an immunostimulatory type regulated cell death activates innate system. A hallmark pyroptosis release intracellular contents such as cytokines, alarmins, chemokines can stimulate adaptive activation. Recent studies suggest promotes Here, we review mechanisms by which be induced highlight induce cells defense. We discuss how modulates tumor microenvironment immunity also research areas focus on continued development anticancer treatment. Pyroptosis-based therapies offer promising avenue treating immunologically 'cold' tumors.

Language: Английский

Citations

8
Unanticipated Loss of Inflammasomes in Birds DOI Creative Commons
Zachary P. Billman, Dustin C. Hancks,

Edward A Miao

et al.

Genome Biology and Evolution, Journal Year: 2024, Volume and Issue: 16(7)

Published: July 1, 2024

Abstract Inflammasomes are multiprotein complexes that form in response to ligands originating from pathogens as well alterations of normal cell physiology caused by infection or tissue damage. These structures engage a robust inflammatory immune eradicates environmental microbes before they cause disease, and slow the growth bona fide pathogens. Despite their undeniable utility immunity, inflammasomes radically reduced birds. Perhaps most surprising is that, within all birds, NLRP3 retained, while its signaling adapter ASC lost, suggesting signals via novel unknown adapter. Crocodilian reptiles turtles, which share more recent common ancestor with retain many lost inflammasome components, indicating deletion occurred after birds diverged crocodiles. Some bird lineages have even extensive loss, songbirds continuing pare down until only CARD8 remain. Remarkably, caspase-1 but downstream targets caspase-1: IL-1β, IL-18, YVAD-linker encoding gasdermin A. This suggests can signal through alternative proteases activate cytokine maturation pyroptosis songbirds. observations may reveal new contexts activation be relevant mammalian suggest avenues research uncover enigmatic nature poorly understood inflammasome.

Language: Английский

Citations

3
Caspase 3 proteolytically inactivates gasdermin Ec and inhibits pyroptosis in an early vertebrate DOI Creative Commons
Xin Tian, Shuai Jiang

Comparative Immunology Reports, Journal Year: 2025, Volume and Issue: unknown, P. 200216 - 200216

Published: March 1, 2025

Language: Английский

Citations

0
Pyroptosis: molecular mechanisms and roles in disease DOI Creative Commons
Petr Brož

Cell Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Language: Английский

Citations

0
Pyroptosis: Induction and inhibition strategies for immunotherapy of diseases DOI Creative Commons
Junjun Wu, Hong Wang, Pu Gao

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4195 - 4227

Published: June 28, 2024

Cell death is a central process for organismal health. Pyroptosis, namely pyroptotic cell death, recognized as critical type that disrupts membrane and triggers pro-inflammatory cytokine secretion

Language: Английский

Citations

2
Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis DOI Creative Commons
Xinran Li, Wei Li, Cong Xiang

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114728 - 114728

Published: Sept. 1, 2024

Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage gasdermin proteins B-E (GSDMB-GSDME) well established as trigger pyroptosis, but the intracellular activation mechanism GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced GSDMA. Nutrient stresses stimulate via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation Ser353 on human ULK1 or phospho-mimetic Ser353Asp mutant liberates from auto-inhibition, facilitating its membrane targeting initiation pyroptosis. To further validate significance phosphorylation, generated constitutively active Ser354Asp mouse Gsdma, which induced skin inflammation hyperplasia in mice, reminiscent phenotypes with activated Gsdma. This study uncovers underlying cellular response to nutrient stress.

Language: Английский

Citations

2