Gsdme
Domain
Intramolecular interactions between N- and C-terminal domains may be important for autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain, that is released upon cleavage by CASP3 or granzyme B (GZMB).
Function
Gasdermin-E
Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis. This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-E, N-terminal) binds to membranes and forms pores, triggering pyroptosis.
Gasdermin-E, N-terminal
Pore-forming protein produced by cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, respectively (PubMed:32188940). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukins (IL1B and IL16) and triggering pyroptosis (PubMed:33852854). Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (By similarity). Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis (PubMed:32188940). Mediates secondary necrosis downstream of the mitochondrial apoptotic pathway and CASP3 activation as well as in response to viral agents (PubMed:28045099). Exhibits bactericidal activity (By similarity). Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity (PubMed:32188940). Suppresses tumors by mediating granzyme-mediated pyroptosis in target cells of natural killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target cells from NK-cells, triggers pyroptosis of tumor cells and tumor suppression (By similarity). May play a role in the p53/TP53-regulated cellular response to DNA damage (By similarity).
Post-translational modifications
Cleavage at Asp-270 by CASP3 (mature and uncleaved precursor forms) or granzyme B (GZMB) relieves autoinhibition and is sufficient to initiate pyroptosis.
Gasdermin-E
Succination 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.
Gasdermin-E
Ubiquitinated on Lys-120 and Lys-189 via 'Lys-48'-linked polyubiquitin chains, leading to proteasomal degradation. Deubiquitinated by USP48, leading to increased stability.
Palmitoylated.
Sequence Similarities
Belongs to the gasdermin family.
Tissue Specificity
Expressed in spleen, kidney, large and small intestine, testicle, stomach and by CD4(+)CD(8+) T cells in thymus (PubMed:28459430). Expressed by macrophages (PubMed:28045099).
Cellular localization
- Gasdermin-E, N-terminal
- Cell membrane
- Multi-pass membrane protein
- Gasdermin-E
- Cytoplasm
- Cytosol
Alternative names
Dfna5, Dfna5h, Gsdme, Gasdermin-E, Non-syndromic hearing impairment protein 5 homolog