Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion
By Wan-ting He, H. Wan, Lichen Hu, Pengda Chen, Xin Wang, Zhe Huang, Zhang-Hua Yang, Chuan-Qi Zhong, Jiahuai Han. Cell Research, 2015
2,265 citations recorded by the source corpus.
Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd−/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd−/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.
Subfields: Molecular Biology, Nephrology
View Paper: https://www.semanticscholar.org/paper/09d5299058952a4f2e52daf1dada062dc8675b4d
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Citations in the corpus
- The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “In addition to cytoskeletal rearrangements, recent studies have identified NEK7, a protein involved in cell-cycle progression, as a novel regulator of the NLRP3 inflammasome (He et al., 2016; Schmid-Burgk et al., 2016; Shi et al., 2016).”
- Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes (2020, neutral): “Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells.”
- Pyroptosis: mechanisms and diseases (2021, background): “On the other hand, caspase-1 also cleaves the precursors of IL-1β and IL-18 to be the mature IL1β and IL-18, which are released through the pores formed by GSDMD, resulting in pyroptosis.(3,4,11,29,31,40) Notably, after inflammasome activation, cells may undergo pyroptosis or release cytokines witho”
- A guide to cell death pathways (2023, positive): “Release of pro-inflammatory factors, such as mature IL-1β, through gasdermin pores occurs via a charge-based mechanism independently of cell death 111,112 .”
- Caspases in cell death, inflammation and disease (2019, background): “Akin to caspase-1-deficient macrophages, deletion of GSDMD similarly reroutes the inflammasome-induced cell death response to apoptosis (de Vasconcelos et al., 2019a; He et al., 2015).”
- The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “Pyroptosis forces intracellular pathogens out of their replicative niche, exposing them to other immune factors, and it also triggers cytokine release and the generation of DAMPs to further prepare the immune system to respond to infection [18,19].”
- Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection (2018, background): “With the discovery that caspase11 drives pyroptosis via activation of the pore-forming protein gasdermin D (GSDMD) (12), the NLRP3 inflammasome was found to activate as a consequence of plasma membrane rupture and the concurrent efflux of potassium ions (21).”
- Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation (2016, positive): “Caspase-1 processes pro-IL-1b and pro-IL-18 into active forms and cleaves gasdermin D to trigger pyroptosis, an inflammatory cell death (He et al., 2015; Kayagaki et al., 2015; Shi et al., 2015).”