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GSDMD

OverviewProducts

Developmental stage

Expression starts at 8.5 dpc and increases from 13.5 dpc on. Still detected after birth.

Domain

Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1 or CASP4/CASP11 (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:29576317, PubMed:31097341). The linker helix loop inserts into the N-terminal domain (By similarity). The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases (PubMed:26375003, PubMed:26375259, PubMed:26611636).

Function

Gasdermin-D

Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190).

Gasdermin-D, N-terminal

Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190, PubMed:32820063). Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4/CASP11 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190). After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27383986, PubMed:27339137). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature IL1B and triggering pyroptosis (PubMed:27383986). Exhibits bactericidal activity (PubMed:27383986). Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27383986). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (PubMed:27383986). Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation (PubMed:30361383, PubMed:30381458). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27383986).

Post-translational modifications

Cleavage at Asp-276 by CASP1 (mature and uncleaved precursor forms), CASP4/CASP11 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375259, PubMed:26611636, PubMed:32554464, PubMed:32553275). Cleavage by CASP1 and CASP4/CASP11 is not strictly dependent on the consensus cleavage site on GSDMD but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32554464, PubMed:32553275). Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ (PubMed:30361383, PubMed:30381458). Cleavage at Asp-88 by CASP3 or CAPS7 inactivates the ability to mediate pyroptosis (By similarity).

Gasdermin-D

Succination of Cys-192 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis (PubMed:32820063). Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate (PubMed:32820063).

Sequence similarities

Belongs to the gasdermin family.

Cellular localization

  • Gasdermin-D
  • Cytoplasm
  • Cytosol
  • Inflammasome
  • In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor.
  • Gasdermin-D, N-terminal
  • Cell membrane
  • Multi-pass membrane protein
  • Secreted
  • Released in the extracellular milieu following pyroptosis.
  • Gasdermin-D, C-terminal
  • Cytoplasm
  • Cytosol

Alternative names

  • Gasdermin-D
  • Gasdermin domain-containing protein 1
  • Gsdmd
  • Gsdmdc1

Database links

Target type

Proteins

Primary research area

Immunology & Infectious Disease

Other research areas

  • Immuno-oncology

Molecular weight

53238Da