GSDME

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene.

Gasdermin E

Gasdermin-E:
Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis (PubMed:27281216, PubMed:28459430).

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 (PubMed:28459430).

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:27281216, PubMed:28459430, PubMed:32188940).

After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:28459430, PubMed:32188940).

Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:28459430).

Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis (PubMed:27281216, PubMed:28459430, 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 (PubMed:27281216).

Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity (PubMed:21522185, 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 (PubMed:32188940, PubMed:31953257).

May play a role in the p53/TP53-regulated cellular response to DNA damage (PubMed:16897187).

Cell death Source: UniProtKB
Cellular response to tumor necrosis factor Source: UniProtKB
Cellular response to virus Source: UniProtKB
Granzyme-mediated programmed cell death signaling pathway Source: UniProtKB
Inner ear receptor cell differentiation Source: Ensembl
Necrotic cell death Source: UniProtKB
Negative regulation of cell population proliferation Source: UniProtKB
Positive regulation of immune response to tumor cell Source: UniProtKB
Positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
Positive regulation of MAPK cascade Source: UniProtKB
Pyroptosis Source: UniProtKB
Sensory perception of sound Source: ProtInc

Gasdermin-E, N-terminal: Cell membrane
Gasdermin-E: Cytosol

Deafness, autosomal dominant, 5 (DFNA5):
A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.

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 (PubMed:32820063). Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate (PubMed:32820063).