Work

Chemically induced dimerization of GSDMD C-terminal domain blocks GSDMD N-terminal domain-mediated pyroptosis

Year: 2025

Type: article

Abstract: GSDMD is a pyroptosis executioner in which the C-terminal domain completely inhibits the pore-forming ability of the N-terminal domain. Caspase cleavage separates GSDMD into the free C-terminal fragment (GD-CT) and the free N-terminal fragment (GD-NT). Although GD-CT retains the ability to bind with GD-NT, it can no longer completely disable GD-NT, allowing the latter to oligomerize and form nano-sized pyroptotic pores in the plasma membrane. In this study, we report that GD-CT is strictly confined to the cytoplasm, whereas GD-NT is transported to the plasma membrane. Additionally, GD-CT undergoes rapid degradation via the 26S proteasome pathway. Therefore, we propose that the spatial separation and rapid turnover of GD-CT limit its efficacy in blocking GD-NT-mediated pyroptosis. Given these properties of GD-CT, we engineered an efficient pyroptosis blocker "FKBP-GD-CT". This chimera protein incorporates a myristoylation motif, which confers plasma membrane translocation capability, and an FKBP12F36V domain, which enables dimerization in response to the chemical inducer AP20187. This is the first report utilizing chemical-induced dimerization technology to modulate pyroptosis levels.

Source: Cell Death Discovery

DOI: 10.1038/s41420-025-02733-0