Gasdermin-C, a member of the gasdermin family of membrane-permeabilizing proteins, originally cloned from metastatic melanoma cells as MLZE. Like other gasdermins it is a two-domain, autoinhibited cytosolic zymogen in which the C-terminal domain masks the lipid-binding surface of the N-terminal domain; proteolysis in the interdomain linker releases the N-terminal fragment, which binds membranes and homo-oligomerizes into a large transmembrane pore. Several proteases have been reported to perform this cleavage in different settings - caspase-8 downstream of TNF and of the metabolite alpha-ketoglutarate, granzyme B in melanoma cells, and cathepsin S in intestinal epithelium - and the physiological consequence of cleavage is disputed. In cancer cells the released fragment forms plasma-membrane pores and executes pyroptosis, whereas in intestinal epithelial cells, where the protein is expressed at steady state and induced by helminth infection, the cleaved fragment instead targets Rab7-positive late endosomal vesicles, alters lipid-droplet turnover and amplifies type 2 immunity without lysis being the main outcome. GSDMC differs from the other gasdermins by a one-residue-shorter lipid-binding motif in the beta1-beta2 loop, and restoring the missing residue increases oligomerization and killing, which suggests that weak pore-forming activity is an intrinsic property of this paralog rather than an experimental artefact. A nuclear, chromatin-associated scaffolding role has also been proposed but is so far supported by a single study. GSDMC is expressed mainly in trachea, spleen, oesophagus, gastric and intestinal epithelium, and its overexpression is associated with poor outcome in several carcinomas.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0042742 defense response to bacterium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level phylogenetic transfer of antibacterial defence to GSDMC. The donor genes carry the evidence; GSDMC itself does not. Reason: The WITH/FROM donors for this row resolve to mouse Gsdmd (MGI:MGI:1916396), human GSDMA (UniProtKB:Q96QA5) and human GSDMB (UniProtKB:Q8TAX9) - all three of which do have direct antibacterial evidence. GSDMC is not among the donors, and no published work assigns GSDMC an antibacterial role. The one in-vivo immune function documented for GSDMC is anti-helminth type 2 immunity in the gut (PMID:40701157), a different arm of mucosal defence. Retained rather than removed because an IBA encodes a PAINT curator's judgement about where in the gasdermin tree the function arose, and that node placement could not be inspected here; demoted to non-core because there is no GSDMC-specific support. Flagged for PAINT re-examination in suggested_questions. |
| GO:0070269 pyroptotic inflammatory response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GSDMC can execute pyroptosis, but whether pyroptosis is its physiological default is the central open dispute about this protein. Reason: Pyroptotic competence is real and directly demonstrated: caspase-8-cleaved GSDMC binds liposomes and forms visible pores (PMID:32929201), alpha-ketoglutarate drives GSDMC-dependent pyroptosis through DR6/caspase-8 (PMID:34012073), and granzyme-B-cleaved GSDMC executes pyroptosis in melanoma cells under a synthetic Nur77 ligand (PMID:41407678). Against that, Pandey et al. report that in intestinal epithelium - the tissue where GSDMC is actually expressed at steady state - cell death is not the main consequence of cleavage, that the cleaved fragment goes to Rab7+ vesicles rather than the plasma membrane, and that GSDMC carries a one-residue-shorter lipid-binding motif whose completion is what makes it oligomerize and kill (PMID:40701157). A 2025 Immunity commentary frames untangling GSDMC from pyroptosis as the open problem (PMID:41092892). Kept as a genuine capability but demoted from core: the melanoma result shows GSDMC CAN form a lytic pore under a strong artificial trigger, which is not the same claim as pyroptosis being what GSDMC normally does. Note that GSDMC (UniProtKB:Q9BYG8) appears in this row's own WITH/FROM, which is expected and marks experimental grounding on the target itself, not circular support. Supporting Evidence: PMID:32929201 GSDMC is specifically cleaved by caspase-8 with TNFΞ± treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. PMID:40701157 Although IEC cell death is not the main consequence of GsdmC cleavage, inserting a single amino acid (aa) within the lipid-binding motif to match that of the other gasdermins enhanced GsdmC oligomerization and increased GsdmC-mediated cell death. |
| GO:0005546 phosphatidylinositol-4,5-bisphosphate binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inner-leaflet phosphoinositide recognition transferred from GSDMD; no headgroup-resolved measurement exists for GSDMC. Reason: This row is seeded only by GSDMD (MGI:MGI:1916396 mouse Gsdmd and UniProtKB:P57764 human GSDMD). The sole GSDMC-specific lipid experiment is a bulk liposome pellet assay in which the liposomes contained phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and PI(4,5)P2 mixed together (PMID:32929201), so it demonstrates membrane binding by the cleaved N-terminal fragment but cannot attribute it to any one headgroup. The transfer is also specifically challenged by the observation that GSDMC's beta1-beta2 lipid-binding motif is one residue shorter than in the other gasdermins and that completing it improves oligomerization (PMID:40701157) - i.e. GSDMC may not read inner-leaflet lipids the way GSDMD does. Retained because the node placement in the PANTHER tree was not inspectable here and because family-level lipid binding is plausible, but demoted to non-core pending a GSDMC-specific lipid-specificity measurement. Supporting Evidence: PMID:32929201 the N-terminal domain, but not full-length GSDMC, bound to liposomes, as evidenced by its detection in the liposome pellet |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Same family-level phosphoinositide transfer from GSDMD; not resolved for GSDMC. Reason: Identical situation to GO:0005546: donors are mouse and human GSDMD only, and the only GSDMC lipid data is a mixed-composition liposome binding assay (PMID:32929201) that cannot assign specificity to PI4P. Kept as a family-level inference, demoted to non-core. |
| GO:0001786 phosphatidylserine binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The weakest of the three lipid-binding transfers - a single GSDMD donor and no GSDMC measurement at all. Reason: The WITH/FROM for this row is mouse Gsdmd (MGI:MGI:1916396) plus the family node alone. No study has tested whether GSDMC binds phosphatidylserine specifically; PS was only ever present as one component of a five-lipid liposome mix (PMID:32929201). Retained as a family-level inference rather than removed, in line with the principle that an IBA carries a curator's judgement about node placement that was not inspectable here, but it should not be treated as an established GSDMC molecular function. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Correct location of the autoinhibited full-length precursor. Reason: Full-length GSDMC is a soluble, autoinhibited cytosolic zymogen; this is the compartment from which it is recruited to membranes after cleavage. Consistent with the UniProt subcellular location for the uncleaved form. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma-membrane targeting of the cleaved N-terminal fragment - real in cancer-cell settings, but reported not to occur for the physiologically cleaved intestinal form. Reason: GOA effectively carries both sides of this dispute, since the same term is also present with EXP evidence from PMID:32929201. Caspase-8-cleaved GSDMC does reach the plasma membrane and form pores there in cancer cells (PMID:32929201). However, Pandey et al. report that cathepsin-S cleaved GSDMC does the opposite in intestinal epithelium: instead of localizing to the plasma membrane, the N-terminal fragment targets Rab7+ vesicles (PMID:40701157). Because GSDMC's steady-state expression is epithelial, the plasma-membrane location is retained but demoted to non-core, and a late endosome location is proposed as a NEW annotation. Both plasma membrane rows carry the same action. Supporting Evidence: PMID:40701157 Mechanistically, instead of localizing to the plasma membrane, we showed that cleaved GsdmC targeted Rab7+ vesicles, such as late endosomes. |
| GO:0005886 plasma membrane | EXP PMID:32929201 PD-L1-mediated gasdermin C expression switches apoptosis to ... | KEEP AS NON CORE | Summary: Experimental plasma-membrane localization of the caspase-8-generated N-terminal fragment in cancer cells. Reason: A genuine experimental result that should not be removed: the cleaved fragment binds liposomes, forms EM-visible pores and permeabilizes the cell membrane (PMID:32929201). It is demoted rather than accepted as core because PMID:40701157 reports that the physiologically cleaved intestinal form does not go to the plasma membrane, so plasma-membrane targeting looks context-specific rather than the general behaviour of GSDMC. Same action as the IEA row for this term. Supporting Evidence: PMID:32929201 Upon incubation with caspase-8-cleaved GSDMC, the liposome surface showed multiple pores of regular shape and size |
| GO:0005737 cytoplasm | IDA PMID:11223543 Structure, expression and chromosome mapping of MLZE, a nove... | ACCEPT | Summary: Cytoplasmic localization of full-length GSDMC in the original MLZE cloning paper. Reason: Biologically uncontroversial - the uncleaved gasdermin is a cytosolic zymogen - and the more specific cytosol annotation on this gene says the same thing. Our cache of PMID:11223543 is abstract-only and the abstract does not state the localization (it notes a leucine zipper and two potential nuclear localization signals), but the curator read the full text and the claim is consistent with everything else known about the protein, so it is accepted rather than questioned. |
| GO:0022829 wide pore channel activity | IDA PMID:32929201 PD-L1-mediated gasdermin C expression switches apoptosis to ... | NEW | Summary: Proposed new annotation - the reconstituted pore-forming activity of the cleaved GSDMC N-terminal fragment, which GOA does not currently record at all. Reason: GSDMC has no molecular-function annotation for pore formation despite this being the best-evidenced property of the protein and the one the family is defined by. Hou et al. showed directly that the caspase-8-generated N-terminal fragment, but not the full-length protein, binds liposomes, that the liposome surface then carries regular pores by electron microscopy, and that encapsulated Tb3+ leaks out (PMID:32929201). GO:0022829 is the term GO_Central already uses for the GSDMD pore, so this keeps GSDMC consistent with its paralog. This annotation records competence; the separate question of which membrane the pore forms in, and whether lysis follows, is handled on the localization and pyroptosis rows. Supporting Evidence: PMID:32929201 Upon incubation with caspase-8-cleaved GSDMC, the liposome surface showed multiple pores of regular shape and size PMID:32929201 the N-terminal domain, but not full-length GSDMC, bound to liposomes, as evidenced by its detection in the liposome pellet |
| GO:0005770 late endosome | IDA PMID:40701157 Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles ... | NEW | Summary: Proposed new annotation - the cleaved N-terminal fragment targets and penetrates Rab7+ late endosomal vesicles. Reason: This is the localization claim at the heart of the current dispute and it is entirely absent from GOA. Pandey et al. imaged RFP-tagged cathepsin-S-generated human GSDMC N-terminal fragment colocalizing with and penetrating into Rab7+ vesicles in HeLa cells, reproduced the result with murine GSDMC2 and GSDMC4 N-terminal fragments and in C. elegans, and showed that Rab7 inhibition rescues the type 2 immune phenotype of Gsdmc-null mice. Rab7+ vesicles are identified in the paper as largely late endosomes. Proposed conservatively as a location only; the downstream lipid-droplet and type 2 immunity processes are left for experts to adjudicate. Supporting Evidence: PMID:40701157 Mechanistically, instead of localizing to the plasma membrane, we showed that cleaved GsdmC targeted Rab7+ vesicles, such as late endosomes. PMID:40701157 Red fluorescent protein (RFP)-tagged CTSS-generated GSDMCN-ter colocalized with, and even penetrated into Rab7+ vesicles, when expressed in HeLa cells, unlike full-length GSDMC |
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Download this section (compressed HTML)Q: Does cleaved GSDMC form a pore in the limiting membrane of Rab7+ late endosomes, or does it permeabilize them by some non-pore mechanism? The Pandey data show penetration into and enlargement of Rab7+ vesicles and loss of vesicle integrity, but the pore itself has only ever been reconstituted on plasma-membrane-mimetic liposomes.
Suggested experts: Reinhard Hinterleitner, Yi-Nan Gong
Q: Is the choice between plasma membrane and Rab7+ vesicle set by the activating protease (caspase-8 or granzyme B versus cathepsin S), by the cleavage position, or by the cell type? All three proteases have now been reported, generating fragments of potentially different lengths.
Suggested experts: Surya P. Pandey, Qiao Wu
Q: What lipid does the GSDMC N-terminal fragment actually recognize? The three phospholipid-binding terms on this gene are family-level transfers from GSDMD, and the only GSDMC experiment used a five-component liposome mix. Given that GSDMC's beta1-beta2 lipid-binding motif is one residue shorter than in the rest of the family, a headgroup-resolved measurement could settle whether the GSDMD paradigm applies at all.
Q: Is the proposed nuclear scaffolding function of GSDMC (import via IPO7-KPNB1-NUP93, recruitment of NAT10 and of BAZ1B/SMARCA5) reproducible outside the originating laboratory, and is it a property of full-length GSDMC or of a cleavage fragment? This would be a major departure from gasdermin biology and currently rests on one paper.
Q: Should the PAINT annotation of defense response to bacterium (GO:0042742) extend to GSDMC? The donors are GSDMD, GSDMA and GSDMB, none of which is GSDMC, and GSDMC's documented in-vivo immune role is anti-helminth type 2 immunity rather than antibacterial defence.
Experiment: Reconstitute purified cathepsin-S-cleaved human GSDMC N-terminal fragment with single-headgroup liposomes (separately PI4P, PI(4,5)P2, phosphatidylserine, phosphatidylinositol, bis(monoacylglycero)phosphate and cardiolipin) rather than a mixed-lipid preparation, and measure binding by co-sedimentation and permeabilization by dye release. Compare side by side with caspase-8-cleaved GSDMC and with GSDMD. Follow with cryo-EM of any pore that forms, to test whether the one-residue-shorter beta1-beta2 motif changes oligomer number or geometry.
Hypothesis: The GSDMC N-terminal fragment forms bona fide transmembrane pores in late endosomal membranes, and its lipid specificity differs from that of GSDMD.
Type: Liposome reconstitution and cryo-electron microscopy
Experiment: Express a panel of defined human GSDMC N-terminal fragments corresponding to the caspase-8, granzyme B and cathepsin S cleavage positions in the same cell background, and score subcellular targeting (plasma membrane versus Rab7/LAMP1 compartments) by live imaging alongside LDH release and endosomal integrity reporters. Include the single-residue beta1-beta2 insertion mutant as a gain-of-lysis control.
Hypothesis: Whether GSDMC lyses the cell or permeabilizes late endosomes is decided by the activating protease and the resulting fragment boundary, not by the cell type.
Type: Structure-function and live-cell imaging
Experiment: Independently test the nuclear model with subcellular fractionation plus quantitative imaging in an unrelated laboratory's LUAD lines, endogenous-tag GSDMC to avoid overexpression artefacts, and run CUT&RUN or ChIP-seq for GSDMC alongside NAT10 and SMARCA5. Ask specifically whether nuclear GSDMC is full-length or a cleavage product, and whether import depends on the leucine zipper and the two predicted nuclear localization signals noted in the original MLZE description.
Hypothesis: GSDMC is present in the nucleus and associates with chromatin in lung adenocarcinoma cells under nutrient stress or irradiation.
Type: Subcellular fractionation, endogenous tagging and chromatin profiling
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