Pyroptosis is a form of lytic programmed cell death executed by a family of pore-forming proteins named gasdermin(GSDM).Pyroptosis plays crucial roles in host defense against pathogen infection and eliminating abnormal and harmful cells,while excessive pyroptosis causes inflammatory diseases including cytokine storm and septic shock.Mammalian GSDMs,except for pejvakin(PJVK),adopt an autoinhibited two-domain architecture,in which the N-terminal cytotoxic domain(GSDM-N)is restrained in an inactive state by the intramolecular interaction with the C-terminal inhibitory domain(GSDM-C).These two-domain proteins are activated by upstream protease cleavage within the interdomain linkers.The unleashed GSDM-N binds to acidic phospholipids in the cytoplasmic leaf of plasma membranes and undergoes dramatic conformational changes and oligomerization,then assembling into transmembrane pores for pyroptosis induction.GSDM pores lead to membrane rupture,cell swelling,and cytosol release,thereby mobilizing proinflammatory responses.GSDMs are evolutionarily conserved and have been discovered across all kingdoms of life,including bacteria,fungi,invertebrates such as cnidarians and mollusks,and all vertebrates.Proteolytic cleavage to liberate the pore-forming activity of GSDM-N appears to be a universal mechanism for most GSDMs activation,despite low sequence homology among the GSDMs from diverse species.However,recent studies discover that there exist noncanonical GSDMs lack of functional C-terminal inhibitory domains in some lower eukaryotic species.These noncanonical GSDMs are activated by unprecedent mechanisms independent of proteolytic cleavage.TrichoGSDM,present in the basal metazoan Trichoplax adhaerens,is a pore-forming domain-only protein and exists as a disulfides-linked autoinhibited dimer.Reduction of the disulfides by the conserved cytoplasmic antioxidant system,including glutathione(GSH)and thioredoxin(Trx),generates pore-forming active monomers capable of inducing lytic cell death.In filamentous fungus Neurospora crassa,polymorphic regulator of cell death-1(rcd-1)encodes two GSDM-like proteins RCD-1-1 and RCD-1-2 in incompatible haplostrains,which trigger pyroptosis-like cell death in nonself discrimination(allorecognition)upon encountering during somatic cell fusion.RCD-1-1 and RCD-1-2 are both monomers and structurally similar to mammalian GSDM-N domains,lacking autoinhibitory fragments.They alone could bind acidic phospholipids,and associate with cell membrane in a resting state.Coexistence of RCD-1-1 and RCD-1-2 leads to formation of RCD-1-1/RCD-1-2 heterodimers through molecular mating,which further oligomerize into membrane-inserted pores,causing rapid lytic cell death.These findings reveal mechanistic diversities in GSDM activation and indicate versatile functions of GSDMs.Due to the highly proinflammatory nature of pyroptosis,the pore-forming activities of GSDMs have been illustrated to be precisely regulated at multiple levels.GSDMD transcription and expression is characterized to be induced by interferon regulatory factors 2(IRF2).mRNA alternative splicing of GSDMB generates various isoforms,some of which exhibit potent pore-forming activity whereas the others bear none.Additionally,different types of post-translational modifications have been identified on GSDMs,playing distinct regulatory roles.For examples,itaconation of GSDMD,succinylation of GSDMD and GSDME,and phosphorylation of GSDMA,GSDMD and GSDME,negatively regulate GSDM pore formation,thereby inhibiting pyroptosis.Conversely,palmitoylation of GSDMD and GSDME,and ubiquitination of GSDMD promote the pore-forming activities and pyroptosis.Moreover,some proteases can cleave within the GSDM-N domains to block their pore-forming activities.On the other hand,bacterial pathogens evolve specific effectors to hijack host pyroptotic defense pathway through targeting upstream caspases,GSDMs or plasma membrane phospholipids.Given the crucial roles of GSDMD in immune defense and pathological inflammation,a few small-molecule inhibitors have been found to directly inhibit GSDMD activity.Since the identification of GSDMs as the executioners of pyroptosis,the GSDM family has attracted broad attention in immunology researches.Significant progress has been made to greatly advance our knowledge about how GSDMs action,and what are the immunological functions of pyroptosis.Investigations of GSDM-targeting therapies are emerging as a promising translational direction.In this paper,we review recent progress in the field of pyroptosis researches,with focus on various molecular mechanisms underlying GSDMs activation and regulation.The biological implication and future direction of pyroptosis research are also discussed.
万方数据
维普
