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

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 the

SUBMITTER: Xu J 

PROVIDER: S-EPMC12518871 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature