GSDMA

GSDMA is a pore-forming gasdermin that executes pyroptosis in epithelial cells, most prominently keratinocytes, where it functions as a direct sensor of bacterial virulence proteases (PMID:35110732, PMID:35545676). The group A Streptococcus cysteine protease SpeB cleaves GSDMA after Gln246, liberating an N-terminal fragment that inserts into membranes to form lytic pores; this allows GSDMA to trigger keratinocyte death independently of host caspases, and Gsdma-deficient mice show uncontrolled GAS dissemination (PMID:35110732, PMID:35545676). Membrane engagement of the N-terminal fragment is reinforced by S-acylation at conserved N-terminal cysteines, a modification that promotes membrane anchoring and oligomerization, can occur directly through palmitoyl-CoA without a palmitoyltransferase, and is reversed by the deacylase ABHD17A, which thereby sets a dynamic S-acylation cycle controlling pore formation (PMID:41972293, PMID:41279037). Beyond host defense, GSDMA acts as a growth-suppressive and pyroptosis-inducing factor in epithelial tumors: it inhibits gastric cancer cell colony formation (PMID:19051310), is required downstream of the RNA-binding protein RBM47 for mesenchymal-to-epithelial transition, suppression of colorectal cancer migration/invasion, and chemosensitization (PMID:41681975), and is antagonized by FAM111B, whose trypsin protease domain binds and degrades GSDMA to promote esophageal cancer progression and cisplatin resistance (PMID:37672204). GSDMA expression is set transcriptionally by promoter DNA methylation (PMID:28241063) and post-transcriptionally by RBM47-mediated mRNA stabilization (PMID:41681975), and the protein contributes to epidermal homeostasis, since its overexpression in mouse skin causes epidermal hyperplasia (PMID:23979942).

1. 2009 Medium

   Established GSDMA as a functionally active, growth-suppressive member of the gasdermin family rather than an inert paralog, distinguishing it from the closely related GSDMB.

   Evidence Colony formation assay in gastric cancer cells transfected with GSDM family members

   PMID:19051310

   Open questions at the time

   • Did not define the molecular mechanism of growth inhibition
   • No connection yet to pore formation or pyroptosis
   • Single assay in one cancer cell context
2. 2013 Medium

   Localized GSDMA expression to hair follicle inner root sheath and suprabasal keratinocytes and linked it to epithelial maintenance, showing gain-of-function causes epidermal hyperplasia while loss-of-function is phenotypically silent.

   Evidence Gsdma knockout and transgenic overexpression mice with skin histology

   PMID:23979942

   Open questions at the time

   • Mechanism linking GSDMA to hyperplasia not defined
   • No activating protease or cleavage event identified
   • Redundancy among mouse Gsdma paralogs unresolved
3. 2017 Medium

   Identified a transcriptional control point for GSDMA, showing that promoter DNA methylation represses its expression and that demethylation restores it across epithelial cell lines.

   Evidence 5-aza-dC treatment with RT-PCR and promoter methylation assays in NuLi-1, 293T, MCF-7

   PMID:28241063

   Open questions at the time

   • Did not identify the methyltransferases or physiological signals controlling methylation
   • No link to downstream functional consequence
4. 2022 High

   Defined GSDMA's core mechanism: it is a direct sensor and substrate of the GAS protease SpeB, which cleaves after Gln246 to release an N-terminal fragment that forms lytic membrane pores and drives keratinocyte pyroptosis as an anti-bacterial defense.

   Evidence In vitro cleavage and membrane permeabilization assays, Gln246 mutagenesis, and Gsdma knockout mice with GAS infection, replicated in two concurrent Nature papers

   PMID:35110732 PMID:35545676

   Open questions at the time

   • Did not resolve how the cleaved fragment anchors to and oligomerizes in membranes
   • Endogenous host proteases activating GSDMA not defined
   • Structure of the GSDMA pore not determined
5. 2023 Medium

   Revealed a degradative regulatory mechanism, showing FAM111B binds GSDMA and degrades it via its trypsin protease domain to suppress GSDMA's tumor-suppressive activity and promote cancer progression.

   Evidence Co-IP/binding assays, Western blot, siRNA knockdown, and xenografts in esophageal cancer models

   PMID:37672204

   Open questions at the time

   • Direct proteolysis of GSDMA by FAM111B not shown biochemically
   • Cleavage site/products undefined
   • Single-lab cancer-model evidence
6. 2026 High

   Defined the membrane-targeting step of GSDMA pore formation, showing S-acylation of conserved N-terminal cysteines promotes anchoring and oligomerization via direct palmitoyl-CoA reaction and is reversed by the deacylase ABHD17A.

   Evidence In vitro S-acylation reconstitution with recombinant protein and palmitoyl-CoA, cysteine mutagenesis, membrane/oligomerization assays, and ABHD17A knockdown

   PMID:41279037 PMID:41972293

   Open questions at the time

   • Physiological enzymes/signals controlling the acylation cycle in vivo not established
   • Stoichiometry/structure of the acylated oligomer undefined
7. 2026 Medium

   Established a post-transcriptional activation axis, showing RBM47 binds the GSDMA 3'-UTR to stabilize its mRNA, and that GSDMA is required downstream for mesenchymal-to-epithelial transition, suppression of CRC invasion, pyroptosis, and chemosensitization.

   Evidence RNA-Seq, RBM47 knockdown/overexpression with GSDMA knockdown rescue, migration/invasion, pyroptosis, and oxaliplatin sensitivity assays

   PMID:41681975

   Open questions at the time

   • Protease activating GSDMA in this CRC context not identified
   • Direct binding site on the 3'-UTR not mapped at nucleotide resolution
   • Single-lab epistasis evidence

• The endogenous host proteases that activate GSDMA in human epithelial homeostasis and tumor suppression, and the high-resolution structure of the assembled GSDMA pore, remain unresolved.
• No host activating protease characterized outside bacterial SpeB
• No structural model of the GSDMA pore
• In vivo physiological triggers of the S-acylation cycle unknown