title: 'Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death.
abstract: Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.
authors.affiliation: Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.|Department of Biochemistry and Molecular Biology, Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China.
authors.forename: Shiqiao
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Stomatology, Jinan University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.|Department of Biochemistry and Molecular Biology, Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China.
authors.forename: Feiyue
authors.initials: F
authors.lastname: Xing
mesh_terms: D001343:Autophagy; D020169:Caspases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D028044:Phosphate-Binding Proteins; D000069292:Pyroptosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D020169:Caspases; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D028044:Phosphate-Binding Proteins; D011960:Receptors, Estrogen; D029701:Saccharomyces cerevisiae Proteins; D016212:Transforming Growth Factor beta; C485887:GSDMA protein, human; D000094524:Gasdermins; C498366:GSDMD protein, human; C111432:GSDME protein, human