Alapfogalmak
Gasdermin D is activated for pore formation and pyroptosis through reversible S-palmitoylation, which can occur on both the cleaved N-terminal domain and the intact full-length protein.
Kivonat
The content discusses the role of S-palmitoylation in the activation of gasdermin D (GSDMD), a key effector of inflammasome-induced pyroptosis and cytokine secretion. Key highlights:
- GSDMD Cys191 is S-palmitoylated, and this palmitoylation is required for pore formation by the GSDMD N-terminal domain (GSDMD-NT).
- S-palmitoylation of GSDMD is augmented by mitochondria-generated reactive oxygen species (ROS) and does not affect GSDMD cleavage.
- Surprisingly, the cleavage-deficient D275A GSDMD mutant can also be palmitoylated after inflammasome stimulation or ROS treatment, and can induce pyroptosis, albeit less efficiently than palmitoylated GSDMD-NT.
- Palmitoylated full-length GSDMD can induce liposome leakage and form pores similar in structure to GSDMD-NT pores.
- The palmitoyltransferases zDHHC5 and zDHHC9 mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS.
- The other human gasdermins are also palmitoylated in their N-termini.
- These findings challenge the previous notion that GSDMD cleavage is the only trigger for its activation, and suggest that reversible palmitoylation serves as a general switch for the activation of this pore-forming protein family.
Statisztikák
GSDMD Cys191 is S-palmitoylated.
Palmitoylation is required for GSDMD-NT pore formation.
Cleavage-deficient D275A GSDMD can also be palmitoylated and induce pyroptosis, albeit less efficiently than palmitoylated GSDMD-NT.
zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation.
The expression of zDHHC5 and zDHHC9 is upregulated by inflammasome activation and ROS.
The other human gasdermins are also palmitoylated in their N-termini.
Idézetek
"Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy."
"These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family."