GSDMD (Gasdermin-D) research notes

UniProt: P57764 (GSDMD_HUMAN), 484 aa. HGNC:25697. Chr 8q24.3.
Family: gasdermin family (PANTHER PTHR16399 GASDERMIN). Domains: Gasdermin (PF04598),
Gasdermin_C (PF17708), Gasdermin_pore (IPR040460), Gasdermin_PUB (IPR041263).

Summary of function

GSDMD is the terminal executioner of pyroptosis, a lytic, pro-inflammatory form of
programmed cell death. Full-length GSDMD is an autoinhibited two-domain protein: an
N-terminal pore-forming domain (GSDMD-NT, ~residues 1-275) held inactive by an
intramolecular interaction with the C-terminal repressor domain (GSDMD-CT).
Inflammatory caspases cleave the interdomain linker (at Asp275 by CASP1; also CASP4/CASP5
in the non-canonical, cytosolic-LPS pathway; CASP8 in the Yersinia/TAK1-inactivation
context), releasing GSDMD-NT. The freed N-terminal fragment binds acidic membrane
phospholipids of the inner leaflet, oligomerizes, and inserts to form large
(10-15 nm inner-diameter) transmembrane pores. These pores conduct mature IL-1β and IL-18
out of the cell and drive pyroptosis; terminal membrane rupture (cytolysis) is executed
downstream by NINJ1.

Lipid binding (the membrane-targeting specificity)

GSDMD-NT binds inner-leaflet acidic phospholipids and cardiolipin; it does NOT bind
phosphatidylcholine/phosphatidylethanolamine (outer leaflet), which is why secreted
GSDMD-NT kills bacteria (which expose cardiolipin/PG) but spares neighboring mammalian
cells from the outside PMID:27281216.
- Binds: PI4P, PI(4,5)P2, PI(3,4,5)P3, phosphatidic acid, phosphatidylserine, cardiolipin.
- The specific lipid-binding GO terms (PI4P, PI(4,5)P2, PS, PA, cardiolipin binding) are
all mechanistically supported by the same body of biochemistry.

Structure of the pore (channel activity)

Cryo-EM shows GSDMD-NT forms a ring-shaped transmembrane β-barrel pore that is 31- to
34-fold symmetric, with the 33-subunit pore measuring ~215 Å inner and ~310 Å outer
diameter PMID:33883744. Note
that the 26- to 28-fold / 27-subunit, 180 Å–inner pore in the same paper is GSDMA3,
not GSDMD. UniProt's widely quoted "10-15 nm inner diameter" derives from the earlier
liposome/AFM measurements of PMID:27281216 ("Most gasdermin pores had an inner diameter
of 10–14 nm and contained 16 symmetric protomers"), which were made on gasdermin-N pores
in artificial membranes; the cryo-EM value (21.5 nm) is the larger, structurally resolved
GSDMD assembly. Both numbers are sourced; they are not the same measurement. The pore is a
large, non-selective conduit ("wide pore channel activity", GO:0022829).
- "Gasdermin D pore structure reveals preferential release of mature interleukin-1"
[PMID:33883744, full text available] — cryo-EM structure; IDA support for wide pore
channel activity (GO:0022829), pyroptotic cell death (GO:0141201), plasma membrane
(GO:0005886), positive regulation of inflammatory response (GO:0050729).

Cleavage/activation, PTMs

Subcellular location (by fragment)

Additional biology

GOA annotation assessment orientation

Core molecular functions to capture:
- wide pore channel activity (GO:0022829) — the defining MF, IDA-supported.
- The lipid-binding activities (PI4P, PI(4,5)P2, PS, PA, cardiolipin) — real, but they are
the membrane-targeting mechanism upstream of pore formation; keep as core/contributing.
Core processes:
- pyroptotic inflammatory response (GO:0070269) / pyroptotic cell death (GO:0141201).
- defense response to (Gram-neg / Gram-pos) bacterium; positive regulation of IL-1β
production; positive regulation of inflammatory response.
Locations:
- plasma membrane (the active pore), cytosol (precursor). NLRP3/canonical inflammasome
"part_of" — GSDMD is a substrate/effector recruited at the inflammasome; these are
reasonable but represent recruitment rather than a stable stoichiometric subunit.

protein binding (GO:0005515, IPI)

Multiple IPI "protein binding" rows from interactome screens (PMID:25416956 human
interactome; PMID:31515488; PMID:32296183; PMID:34296442). Uninformative per project
guidelines — mark as over-annotated/non-core (keep, but not core; recommend more specific
MF where a real partner is known).

Key references (verified against UniProt curation / cached full text)

Chimeric trans-fusion: GSDMD:TMEM106A (Gsdmd-Tmem106a)

A 2026 study identified a functional, protein-coding chimeric mRNA fusing GSDMD to an
out-of-frame C-terminal peptide from Tmem106a, formed by RNA-level trans-splicing of
transcripts from two genes on different chromosomes (not a DNA translocation). This is
the worked example from a long-read RNA-seq screen for chimeric transcripts in macrophages
[PMID:42686912, Venezia/Kane et al., Nature 2026]. (An earlier draft of these notes put the
catalogue at ">30,000 chimeric mRNAs"; that figure is not in the cached record, which is
abstract-only, so it has been removed rather than left uncited.)