GSDMD

Summary

GSDMD (gasdermin D, HGNC:25697) is a protein-coding gene on chromosome 8q24.3, encoding Gasdermin-D (P57764). Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals.

Gasdermin D is a member of the gasdermin family. Members of this family appear to play a role in regulation of epithelial proliferation. Gasdermin D has been suggested to act as a tumor suppressor. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 79792 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 135 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_024736

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25697
Approved symbol	GSDMD
Name	gasdermin D
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12150, DF5L
Ensembl gene	ENSG00000104518
Ensembl biotype	protein_coding
OMIM	617042
Entrez	79792

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 20 protein_coding, 7 retained_intron, 1 non_stop_decay

ENST00000262580, ENST00000524846, ENST00000525208, ENST00000525721, ENST00000526051, ENST00000526406, ENST00000526469, ENST00000528475, ENST00000529854, ENST00000531173, ENST00000531184, ENST00000533063, ENST00000533348, ENST00000533888, ENST00000534018, ENST00000534602, ENST00000866629, ENST00000866630, ENST00000866631, ENST00000866632, ENST00000866633, ENST00000917300, ENST00000917301, ENST00000917302, ENST00000967708, ENST00000967709, ENST00000967710, ENST00000967711

RefSeq mRNA: 2 — MANE Select: NM_024736 NM_001166237, NM_024736

CCDS: CCDS34956

Canonical transcript exons

ENST00000262580 — 11 exons

Exon	Start	End
ENSE00000876552	143559777	143559969
ENSE00001412517	143558346	143558451
ENSE00002186401	143562662	143563062
ENSE00003472479	143562209	143562350
ENSE00003474194	143561370	143561423
ENSE00003509541	143561002	143561104
ENSE00003520747	143562448	143562521
ENSE00003522211	143560603	143560771
ENSE00003598871	143561742	143561828
ENSE00003658119	143561959	143562131
ENSE00003674733	143559332	143559552

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.8313 / max 194.4999, expressed in 1621 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91411	20.9830	1619
91410	0.5503	332
91412	0.2980	156

Top tissues by expression

142 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	98.65	gold quality
mucosa of transverse colon	UBERON:0004991	98.10	gold quality
granulocyte	CL:0000094	97.89	gold quality
right lobe of liver	UBERON:0001114	97.47	gold quality
duodenum	UBERON:0002114	96.98	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.86	gold quality
blood	UBERON:0000178	96.78	gold quality
small intestine	UBERON:0002108	96.63	gold quality
right lobe of thyroid gland	UBERON:0001119	96.60	gold quality
apex of heart	UBERON:0002098	96.45	gold quality
upper lobe of left lung	UBERON:0008952	96.28	gold quality
right lung	UBERON:0002167	96.22	gold quality
vermiform appendix	UBERON:0001154	96.21	gold quality
transverse colon	UBERON:0001157	96.21	gold quality
lymph node	UBERON:0000029	96.13	gold quality
endocervix	UBERON:0000458	96.12	gold quality
left lobe of thyroid gland	UBERON:0001120	96.11	gold quality
left ovary	UBERON:0002119	95.94	gold quality
metanephros cortex	UBERON:0010533	95.90	gold quality
right ovary	UBERON:0002118	95.85	gold quality
thyroid gland	UBERON:0002046	95.77	gold quality
right uterine tube	UBERON:0001302	95.71	gold quality
fundus of stomach	UBERON:0001160	95.66	gold quality
body of uterus	UBERON:0009853	95.63	gold quality
omental fat pad	UBERON:0010414	95.58	gold quality
adult mammalian kidney	UBERON:0000082	95.55	gold quality
liver	UBERON:0002107	95.42	gold quality
left uterine tube	UBERON:0001303	95.40	gold quality
colon	UBERON:0001155	95.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.27	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting GSDMD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Study investigated the expression pattern of the GSDM family genes in the upper gastrointestinal epithelium and cancers. (PMID:19051310)
• caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis (PMID:26375003)
• Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1beta in both canonical and non-canonical inflammasome responses. (PMID:26611636)
• GsdmD p30 kills cells by forming pores that compromise the integrity of the cell membrane. (PMID:27339137)
• GSDMD N-terminal cleavage product oligomerizes in membranes to form pores that are visible by electron microscopy (PMID:27383986)
• Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death. (PMID:27418190)
• Studies show that the membrane-pores composed of gasdermin D-N domains (GSDMD-N domain) are required for pyroptosis. (PMID:27460194)
• the gasdermin-D pore: Executor of pyroptotic cell death (PMID:27557502)
• This study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis. (PMID:27573174)
• Studies indicate that gasdermin D (GSDMD) is cleaved by the activated caspases-1/4/5/11 between its N-terminal and C-terminal domains. (PMID:27604419)
• The pyroptosis is redefined as gasdermin D-mediated programmed necrosis. Gasdermin D are associated with various genetic diseases, and their cellular function and mechanism of activation. (PMID:27932073)
• Remarkably, the Enterovirus 71 protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. (PMID:28679757)
• Data, including data from studies using recombinant fusion forms of GSDMD, suggest that GSDMD participates in inflammasome-dependent pyroptosis of macrophages in response to various stimuli; this mechanism involves proteolysis of GSDMD by caspase-1 and caspase-11. (PMID:28726636)
• These findings reveal that GSDMD-C acts as an auto-inhibition executor and GSDMD-N could form pore structures via a charge-charge interaction upon cleavage by caspases during cell pyroptosis. (PMID:28928145)
• Results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of alcoholic hepatitis (PMID:29108122)
• Pyroptosis regulator gasdermin D was necessary for IL-1beta secretion from living macrophages that have been exposed to inflammasome activators, such as bacteria and their products or host-derived oxidized lipids (PMID:29195811)
• Gasdermin D plays a key role in the pathogenesis of non-alcoholic steatohepatitis (NASH) by regulating lipogenesis, the inflammatory response, and the NF-kB signaling pathway, revealing potential treatment targets for NASH in humans. (PMID:29273476)
• GSDMD regulates the release of microparticulate active caspase 1 from monocytes essential for induction of cell death and thereby may play a critical role in sepsis-induced endothelial cell injury. (PMID:29365280)
• Study reports the crystal structure of GSDMD C-terminal domain. Two interaction sites mediate the association of C and N domains. Mutations of GSDMD C-domain residues predicted to locate at its interface with the N-domain enhanced pyroptosis. Results suggest that GSDMDs may employ a distinct mode of intramolecular domain interaction and autoinhibition, which may be relevant to its unique role in pyroptosis. (PMID:29576317)
• The present study not only contributes to our understanding of GSDMD recognition by inflammatory caspases but also reports a specific inhibitor for these caspases that can serve as a tool for investigating inflammasome signaling. (PMID:29891674)
• Once inserted, the N-terminal domain of GSDMD assembles arc-, slit-, and ring-shaped oligomers, each of which being able to form transmembrane pores. This assembly and pore formation process is independent on whether GSDMD has been cleaved by caspase-1, caspase-4, or caspase-5. (PMID:29898893)
• High GSDMD expression is associated with tumor-node-metastasis in nonsmall cell lung cancer. (PMID:30106450)
• GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis. (PMID:30143555)
• lncRNA RP185F18.6 and DeltaNp63 may be considered unfavorable biomarkers, whereas GSDMD may be a favorable biomarker in colorectal cancer (CRC) ; these markers may prove valuable in the future diagnosis and prognosis of CRC (PMID:30226619)
• T. vaginalis inflammasome activation induces macrophage inflammatory cell death by pyroptosis, known to occur via caspase-1 cleavage of the gasdermin D protein, which assembles to form pores in the host cell membrane. We found that T. vaginalis-induced cytolysis of macrophages is attenuated in gasdermin D knockout cells (PMID:30391945)
• role of GSDMD in the stretch-induced inflammatory response in human periodontal ligament cells (PMID:30392072)
• Shiga toxin 2 (Stx2)/Lipopolysaccharide complex, from pathogenic enterohemorrhagic Escherichia coli, activates caspase-4, gasdermin D (GSDMD), and the NLRP3 inflammasome in human THP-1 macrophages. (PMID:30404007)
• our current work demonstrates that IL-1beta release from stimulated THP1 cells is regulated by GSDM-D, and P2X7 is a dual-step process (PMID:30547277)
• findings suggest that NLRP3 is central to the activation/release of active caspase-1/GSDM-D encapsulated in microparticles (MP) by Francisella. (PMID:30596757)
• Our findings provide the first demonstration of GSDMD-determined pyroptotic cell death responsible for I/R induced release of IL-1beta and this would provide a mandate to better understand the unconventional mechanisms of cytokine release in the sterile innate immune system. (PMID:30634142)
• GSDMD is required for an optimal cytotoxic t-lymphocyte response to cancer cells (PMID:31276977)
• Gasdermin D: Evidence of pyroptosis in spontaneous preterm labor with sterile intra-amniotic inflammation or intra-amniotic infection. (PMID:31461796)
• alpha-NETA also significantly increased expression of pyroptosis-associated molecules including caspase-4 and GSDMD in epithelial ovarian cancer cells. (PMID:31480859)
• The GSDMD promotes IL-1 release from hyperactive or pyroptotic cells, with a specific focus on defining how these distinct cell fates associated with GSDMD activity can be regulated. (PMID:31492708)
• Gasdermin D (GSDMD) ontrols the release of the proinflammatory cytokines and pyroptotic cell death [Review]. (PMID:31548300)
• The expression of gasdermin D N terminal domain was significantly increased in the liver during human acute liver failure (ALF), in a D-galactose/lipopolysaccharide (D-Galn/LPS)-induced ALF mouse model and in D-Galn/LPS-treated AML12 hepatocytes. GSDMD-mediated hepatocyte pyroptosis expanded the inflammatory response by upregulating MCP1/CCR2 to recruit macrophages. (PMID:31802832)
• Inactivation of the Cytoprotective Major Vault Protein by Caspase-1 and -9 in Epithelial Cells during Apoptosis. (PMID:31877317)
• Human polymorphisms in GSDMD alter the inflammatory response. (PMID:31988247)
• Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. (PMID:32109412)
• CD147 Expression Is Associated with Tumor Proliferation in Bladder Cancer via GSDMD. (PMID:32149134)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pjvk	ENSDARG00000079945
mus_musculus	Gsdmd	ENSMUSG00000022575
rattus_norvegicus	Gsdmd	ENSRNOG00000007728

Paralogs (4): GSDMB (ENSG00000073605), GSDMC (ENSG00000147697), GSDMA (ENSG00000167914), PJVK (ENSG00000204311)

Protein

Protein identifiers

Gasdermin-D — P57764 (reviewed: P57764)

Alternative names: Gasdermin domain-containing protein 1

All UniProt accessions (8): P57764, E9PIB2, E9PNZ0, E9PQ48, E9PQR9, E9PRF1, G3V1A6, H0YDB0

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals. 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. Promotes pyroptosis in response to microbial infection and danger signals. Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1, CASP4 or CASP5 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators. 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. Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukin-1 (IL1B and IL18) and triggering pyroptosis. Gasdermin pores also allow the release of mature caspase-7 (CASP7). In some, but not all, cells types, pyroptosis is followed by pyroptotic cell death, which is caused by downstream activation of ninjurin-1 (NINJ1), which mediates membrane rupture (cytolysis). Also forms pores in the mitochondrial membrane, resulting in release of mitochondrial DNA (mtDNA) into the cytosol. 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. Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes. Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation. Required for mucosal tissue defense against enteric pathogens. Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown. Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine. Transcription coactivator produced by the cleavage by CASP3 or CASP7 in the upper small intestine in response to dietary antigens. Required to maintain food tolerance in small intestine: translocates to the nucleus and acts as a coactivator for STAT1 to induce the transcription of CIITA and MHC class II molecules, which in turn induce type 1 regulatory T (Tr1) cells in upper small intestine. Produced by the cleavage by papain allergen. After cleavage, moves to the plasma membrane and homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the specific release of mature interleukin-33 (IL33), promoting type 2 inflammatory immune response.

Subunit / interactions. Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane. Homooligomerization is promoted by the mTORC1 complex in macrophages. In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor. Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence.

Subcellular location. Cytoplasm. Cytosol. Inflammasome Cell membrane. Secreted. Mitochondrion membrane Cytoplasm. Cytosol Nucleus Cytoplasm.

Tissue specificity. Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.

Post-translational modifications. Cleavage at Asp-275 by CASP1 (mature and uncleaved precursor forms), CASP4, CASP5 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis. Cleavage by CASP1 and CASP4 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. Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ. Cleavage at Asp-87 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis, but generates the Gasdermin-D, p13 chain, which translocates to the nucleus and acts as a transcription regulator. Cleavage by papain allergen generates the Gasdermin-D, p40 chain. Palmitoylated at Cys-191 by ZDHHC5 and ZDHHC9 in response to microbial infection and danger signals. Palmitoylation takes place before cleavage by caspases (CASP1, CASP4, CASP5 or CASP8) and is required for membrane translocation and pore formation. Depalmitoylated by LYPLA2. Succination of Cys-191 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis. Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate. Glycosylated: O-GlcNAcylation by OGT leads to reduced cleavage by CASP4 and decreased LPS-induced endothelial cell pyroptosis. (Microbial infection) Cleaved and inactivated by Protease 3C from Human enterovirus 71 (EV71), preventing GSDMD-mediated pyroptosis. (Microbial infection) Cleaved and inactivated by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2, preventing GSDMD-mediated pyroptosis. (Microbial infection) Ubiquitinated by S.flexneri IpaH7.8, leading to its degradation by the proteasome.

Activity regulation. The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-D, N-terminal) following cleavage by caspases CASP1, CASP4, CASP5 or CASP8. Cleavage at Asp-87 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis. Homooligomerization and pore formation is specifically inhibited by VHH(GSDMD-1) and, to a lesser extent, VHH(GSDMD-2) nanobodies, protecting against excessive pyroptosis. Inhibited by small molecule NU6300, which covalently reacts with Cys-191, thereby preventing palmitoylation and pyroptosis.

Domain organisation. Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1, CASP4 or CASP5. The linker helix loop inserts into the N-terminal domain. The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases. Forms a ring-shaped pore complex containing 27-28 subunits that inserts into the membrane. The pore conduit is predominantly negatively charged, facilitating the release of mature interleukin-1 (IL1B and IL18). In contrast interleukin-1 precursors are not released, due to the presence of an acidic region that is proteolytically removed by CASP1 during maturation.

Similarity. Belongs to the gasdermin family.

RefSeq proteins (2): NP_001159709, NP_079012* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007677	Gasdermin	Family
IPR040460	Gasdermin_pore	Domain
IPR041263	Gasdermin_PUB	Domain

Pfam: PF04598, PF17708

UniProt features (97 total): mutagenesis site 36, strand 16, helix 15, modified residue 8, chain 5, site 4, transmembrane region 4, turn 3, sequence conflict 2, lipid moiety-binding region 1, glycosylation site 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9E0V	X-RAY DIFFRACTION	1.64
7Z1X	X-RAY DIFFRACTION	1.86
5NH1	X-RAY DIFFRACTION	2.04
5WQT	X-RAY DIFFRACTION	2.64
6KN0	X-RAY DIFFRACTION	2.79
6AO4	X-RAY DIFFRACTION	2.9
6N9O	X-RAY DIFFRACTION	3.5
6KMZ	X-RAY DIFFRACTION	3.61
6VFE	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57764-F1	78.45	0.32

Antibody-complex structures (SAbDab): 1 — 7Z1X

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 87–88 (cleavage; by casp3 or casp7); 193–194 (cleavage; by enterovirus 71 (ev71) protease 3c and coronavirus sars-cov-2 proteinase nsp5); 275–276 (cleavage; by caspases casp1, casp4, casp5 and casp8); 290–291 (cleavage; by papain)

Post-translational modifications (9): 37, 56, 158, 185, 191, 268, 309, 467, 191

Glycosylation sites (1): 338

Mutagenesis-validated functional residues (36):

Position	Phenotype
7–11	impaired pore-formation.
15	no spontaneous pyroptosis-inducing activity; when associated with d-192.
16–22	abolished ubiquitination by s.flexneri ipah7.8.
42–53	abolished ability to form a pore.
48–50	abolished ability to form a pore.
63–73	in ap1; promotes ability to release of interleukin-1 (il1b and il18) precursors.
87–95	in ap2; promotes ability to release of interleukin-1 (il1b and il18) precursors.
104	decreased effectiveness in pore formation and pyroptosis induction. no effect on cleavage by casp1.
174	reduced ability to form a pore.
191	abolished palmitoylation and ability to form a pore and mediate pyroptosis. prevents binding to small molecule nu6300.
192	decreased induction of pyroptosis and defects in liposome-binding. no spontaneous pyroptosis-inducing activity; when ass
193	abolished cleavage by enterovirus 71 (ev71) protease 3c and human coronavirus sars-cov-2 3c-like proteinase nsp5.
204	reduced ability to form a pore.
234	does not affect ability to induce pyroptosis.
235	does not affect ability to induce pyroptosis.
236	does not affect ability to induce pyroptosis.
237	does not affect ability to induce pyroptosis.
238	does not affect ability to induce pyroptosis.
239	abolished ability to induce pyroptosis.
240	abolished ability to induce pyroptosis.
241	does not affect ability to induce pyroptosis.
242	does not affect ability to induce pyroptosis.
243	does not affect ability to induce pyroptosis.
272–274	does not affect interaction with casp4.
275	loss of cleavage by casp1 and casp4 and of lps-induced pyroptosis. does not affect interaction with casp1 and casp4.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-111457	Release of apoptotic factors from the mitochondria
R-HSA-448706	Interleukin-1 processing
R-HSA-5620971	Pyroptosis
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-6798695	Neutrophil degranulation
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9960519	CASP4-mediated substrate cleavage
R-HSA-9960525	CASP5-mediated substrate cleavage

MSigDB gene sets: 215 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, ONKEN_UVEAL_MELANOMA_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CYTOKINE_PRODUCTION, GOBP_PORE_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_SECRETION, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (21): plasma membrane repair (GO:0001778), protein secretion (GO:0009306), positive regulation of interleukin-1 beta production (GO:0032731), defense response to bacterium (GO:0042742), innate immune response (GO:0045087), ceramide biosynthetic process (GO:0046513), pore complex assembly (GO:0046931), positive regulation of inflammatory response (GO:0050729), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), protein homooligomerization (GO:0051260), protein maturation (GO:0051604), pyroptotic inflammatory response (GO:0070269), pyroptotic cell death (GO:0141201), immune system process (GO:0002376), inflammatory response (GO:0006954), programmed cell death (GO:0012501), interleukin-18-mediated signaling pathway (GO:0035655), NLRP3 inflammasome complex assembly (GO:0044546), transmembrane transport (GO:0055085), interleukin-1-mediated signaling pathway (GO:0070498)

GO Molecular Function (8): phosphatidylserine binding (GO:0001786), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), wide pore channel activity (GO:0022829), phosphatidylinositol-4-phosphate binding (GO:0070273), phosphatidic acid binding (GO:0070300), cardiolipin binding (GO:1901612), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (16): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial membrane (GO:0031966), specific granule lumen (GO:0035580), NLRP3 inflammasome complex (GO:0072559), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endomembrane system (GO:0012505), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Non-canonical inflammasome activation	2
Apoptotic factor-mediated response	1
Interleukin-1 family signaling	1
Regulated Necrosis	1
Toll-like Receptor Cascades	1
Innate Immune System	1
Cell recruitment (pro-inflammatory response)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
anion binding	3
defense response	2
inflammatory response	2
defense response to bacterium	2
phospholipid binding	2
phosphatidylinositol phosphate binding	2
binding	2
cytoplasm	2
intracellular organelle lumen	2
intracellular membrane-bounded organelle	2
plasma membrane organization	1
wound healing	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
response to bacterium	1
immune response	1
defense response to symbiont	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
protein-containing complex assembly	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
protein complex oligomerization	1
gene expression	1
protein metabolic process	1
programmed cell death	1
pyroptotic inflammatory response	1
biological_process	1
signal transduction	1
cell death	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-18	1
canonical inflammasome complex assembly	1

Protein interactions and networks

STRING

1346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSDMD	NLRP3	Q96P20	906
GSDMD	CASP1	P29466	905
GSDMD	IL18	Q14116	889
GSDMD	MLKL	Q8NB16	829
GSDMD	AIM2	O14862	817
GSDMD	IL1B	P01584	815
GSDMD	MEFV	O15553	814
GSDMD	CASP8	Q14790	814
GSDMD	RIPK3	Q9Y572	811
GSDMD	NLRC4	Q9NPP4	806
GSDMD	CASP5	P51878	804
GSDMD	NEK7	Q8TDX7	794
GSDMD	NLRP1	Q9C000	789
GSDMD	PYCARD	Q9ULZ3	784
GSDMD	CASP4	P49662	739

IntAct

65 interactions, top by confidence:

A	B	Type	Score
GSDMD	KCTD6	psi-mi:“MI:0915”(physical association)	0.780
KCTD6	GSDMD	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
N	GSDMD	psi-mi:“MI:0915”(physical association)	0.660
N	GSDMD	psi-mi:“MI:0403”(colocalization)	0.660
GSDMD	N	psi-mi:“MI:0915”(physical association)	0.660
GSDMD	N	psi-mi:“MI:0914”(association)	0.660
SFXN5	CTSA	psi-mi:“MI:0914”(association)	0.640
GSDMD	CASP1	psi-mi:“MI:0570”(protein cleavage)	0.590
GSDMD	CASP1	psi-mi:“MI:0915”(physical association)	0.590
GSDMD	ZNF558	psi-mi:“MI:0915”(physical association)	0.560
GSDMD	ZBTB33	psi-mi:“MI:0915”(physical association)	0.560
GSDMD	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
GSDMD	ASPG	psi-mi:“MI:0915”(physical association)	0.560
GSDMD	ZNF426	psi-mi:“MI:0915”(physical association)	0.560
PSMA1	GSDMD	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (41): KCTD6 (Two-hybrid), GSDMD (Reconstituted Complex), MEOX2 (Two-hybrid), PSMA1 (Two-hybrid), ZNF426 (Two-hybrid), ASPG (Two-hybrid), ZNF558 (Two-hybrid), KCTD6 (Two-hybrid), ZBTB33 (Two-hybrid), GSDMD (Affinity Capture-Western), IRAK3 (Affinity Capture-Western), CASP8 (Affinity Capture-Western), CDC37 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), NEDD4 (Affinity Capture-Western)

ESM2 similar proteins: A1L3T7, A2CJ06, C9JE40, O15287, O15482, P33076, P57764, P70434, P79621, P85967, Q00978, Q14653, Q15572, Q2KHK6, Q32M21, Q3TR54, Q3UPH7, Q499Z3, Q4JF28, Q4R3B7, Q571B6, Q5JYT7, Q5PNP6, Q5XIS1, Q5Y4Y6, Q6AXX1, Q6P773, Q6PDZ2, Q7TSI1, Q80VA5, Q8BHW9, Q8BMG1, Q8BTN6, Q8CB12, Q8CE13, Q8CFK6, Q8CIE4, Q8K330, Q8TAX9, Q8TE77

Diamond homologs: P57764, Q32M21, Q5Y4Y6, Q96QA5, Q9BYG8, Q9D8T2, Q9EST1, Q99NB5, Q2KHK6, Q3TR54, Q8CB12, Q8TAX9, P85967

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
“Caspase 1 complex”	“up-regulates activity”	GSDMD	cleavage
CASP4	“up-regulates activity”	GSDMD	cleavage
CASP5	“up-regulates activity”	GSDMD	cleavage
GSDMD	up-regulates	Pyroptosis

Disease & clinical

Clinical variants and AI predictions

ClinVar

135 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	89
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

2077 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143560697:G:GT	donor_gain	1.0000
8:143561350:T:TA	acceptor_gain	1.0000
8:143561356:C:A	acceptor_gain	1.0000
8:143561360:T:TA	acceptor_gain	1.0000
8:143561369:GAC:G	acceptor_gain	1.0000
8:143561729:T:G	acceptor_gain	1.0000
8:143561729:T:TA	acceptor_gain	1.0000
8:143561735:T:TA	acceptor_gain	1.0000
8:143561740:A:AG	acceptor_gain	1.0000
8:143561741:G:GA	acceptor_gain	1.0000
8:143561829:GTC:G	donor_loss	1.0000
8:143561956:CAGAT:C	acceptor_loss	1.0000
8:143561957:A:AG	acceptor_gain	1.0000
8:143561957:AG:A	acceptor_loss	1.0000
8:143561957:AGAT:A	acceptor_gain	1.0000
8:143561957:AGATG:A	acceptor_gain	1.0000
8:143561958:G:GA	acceptor_gain	1.0000
8:143561958:GAT:G	acceptor_gain	1.0000
8:143561958:GATG:G	acceptor_gain	1.0000
8:143561958:GATGG:G	acceptor_gain	1.0000
8:143562075:G:GT	donor_gain	1.0000
8:143562087:G:GT	donor_gain	1.0000
8:143562123:G:GT	donor_gain	1.0000
8:143562126:G:GT	donor_gain	1.0000
8:143562207:A:AG	acceptor_gain	1.0000
8:143562207:AGCT:A	acceptor_gain	1.0000
8:143562208:G:GA	acceptor_gain	1.0000
8:143562208:GCT:G	acceptor_gain	1.0000
8:143562208:GCTG:G	acceptor_gain	1.0000
8:143562308:G:GT	donor_gain	1.0000

AlphaMissense

3102 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143561068:T:C	F216L	0.986
8:143561070:C:A	F216L	0.986
8:143561070:C:G	F216L	0.986
8:143561405:T:C	F240L	0.982
8:143561407:C:A	F240L	0.982
8:143561407:C:G	F240L	0.982
8:143559348:T:C	F5L	0.967
8:143559350:T:A	F5L	0.967
8:143559350:T:G	F5L	0.967
8:143561069:T:C	F216S	0.958
8:143561045:T:C	I208T	0.954
8:143560671:T:A	V160E	0.946
8:143559480:T:C	F49L	0.939
8:143559482:C:A	F49L	0.939
8:143559482:C:G	F49L	0.939
8:143561066:C:A	A215E	0.939
8:143559947:T:A	W130R	0.936
8:143559947:T:C	W130R	0.936
8:143560668:T:A	V159E	0.930
8:143561077:G:C	A219P	0.930
8:143559949:G:C	W130C	0.927
8:143559949:G:T	W130C	0.927
8:143561084:T:A	L221Q	0.927
8:143561406:T:G	F240C	0.926
8:143559517:T:C	I61T	0.923
8:143560662:T:A	V157E	0.921
8:143559451:T:A	L39Q	0.919
8:143561084:T:C	L221P	0.919
8:143559435:T:C	F34L	0.918
8:143559437:C:A	F34L	0.918

dbSNP variants (sampled 300 via entrez): RS1000169538 (8:143556810 T>C), RS1000489955 (8:143554393 C>T), RS1000606581 (8:143556613 G>T), RS1000838537 (8:143558390 G>A,T), RS1000841038 (8:143554542 A>G), RS1000871136 (8:143558254 G>A,C,T), RS1001270473 (8:143563386 G>A,C), RS1001306958 (8:143551926 T>A,C), RS1001645759 (8:143561784 C>T), RS1001661753 (8:143554144 A>T), RS1001701934 (8:143563162 T>A,C), RS1001751536 (8:143558799 G>A), RS1001826754 (8:143558568 C>A,T), RS1002007906 (8:143554297 G>A), RS1002221821 (8:143562313 C>T)

Disease associations

OMIM: gene MIM:617042 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008459_52	Schizophrenia	4.000000e-08
GCST008459_53	Schizophrenia	1.000000e-09
GCST90002393_367	Monocyte count	2.000000e-11
GCST90011898_109	Alanine aminotransferase levels	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523247 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 48,127 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL964	DISULFIRAM	4	38,611
CHEMBL961	DITIOCARB	2	9,516

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Gasdermins (GSDM)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
disulfiram	Inhibition	6.4	pIC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.40	IC50	400	nM	DISULFIRAM
6.40	IC50	400	nM	DITIOCARB

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Disulfiram	1525286: Inhibition of GSDMD in human monocyte/macrophages assessed as inhibition of pyroptosis in presence of Cu2+	ic50	0.4000	uM
diethylcarbamodithioic acid	1525286: Inhibition of GSDMD in human monocyte/macrophages assessed as inhibition of pyroptosis in presence of Cu2+	ic50	0.4000	uM

CTD chemical–gene interactions

96 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetylcysteine	decreases reaction, increases reaction, affects reaction, increases cleavage, increases expression	6
sodium arsenite	decreases reaction, affects binding, increases cleavage, increases expression, increases reaction (+6 more)	5
Adenosine Triphosphate	affects cotreatment, increases cleavage, decreases reaction, increases expression, affects reaction	4
Glucose	affects localization, decreases reaction, increases expression, increases cleavage, affects reaction (+2 more)	4
Lipopolysaccharides	increases cleavage, affects cotreatment, increases expression, increases reaction, decreases reaction	4
bisphenol A	decreases expression, decreases methylation, decreases reaction, increases expression	3
Valproic Acid	decreases expression, increases methylation, affects expression	3
4-phenylbutyric acid	decreases reaction, increases cleavage, increases expression	2
lipopolysaccharide, Escherichia coli O111 B4	increases expression, increases reaction, affects reaction, decreases phosphorylation, decreases reaction (+3 more)	2
benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone	decreases reaction, increases expression, increases cleavage	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Disulfiram	affects binding, decreases activity, affects cotreatment, decreases reaction, increases expression (+1 more)	2
Cadmium Chloride	decreases expression, increases expression, decreases reaction, affects reaction	2
Particulate Matter	affects cotreatment, increases abundance, increases cleavage, decreases reaction	2
tetrachlorobenzoquinone	increases expression, increases secretion, affects localization, decreases reaction, increases cleavage (+1 more)	1
N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide	decreases reaction, increases cleavage	1
SC-66 compound	affects cotreatment, increases abundance, increases cleavage	1
AKT activator SC79	affects cotreatment, increases abundance, increases cleavage	1
graphene oxide	increases expression	1
ML385	decreases reaction, increases cleavage	1
triphenyl phosphate	affects expression	1
titanium dioxide	increases expression	1
divinyl sulfone	increases cleavage	1
ruscogenin	decreases reaction, increases expression	1
plumbagin	increases cleavage, decreases reaction	1
peoniflorin	decreases reaction, increases cleavage	1
zinc protoporphyrin	increases cleavage, decreases reaction	1
saikosaponin D	decreases reaction, increases cleavage	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4321889	Binding	Inhibition of GSDMD in human monocyte/macrophages assessed as inhibition of pyroptosis in presence of Cu2+	Gasdermin D (GSDMD) as a new target for the treatment of infection. — Medchemcomm

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8AQ	THP1-KO-GSDMD	Cancer cell line	Male
CVCL_B5K7	HAP1 GSDMD (-) 2	Cancer cell line	Male
CVCL_D6B6	HyCyte GES-1 KO-hGSDMD	Transformed cell line	Sex unspecified
CVCL_D9WW	Ubigene HTR-8/SVneo GSDMD KO	Transformed cell line	Sex unspecified
CVCL_E1CY	Ubigene THP-1 GSDMD KO	Cancer cell line	Male
CVCL_E1MZ	HyCyte THP-1 KO-hGSDMD	Cancer cell line	Male
CVCL_XP40	HAP1 GSDMD (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.