Gasdermin D pore-forming activity is redox-sensitive.

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Inflammasomes are crucial innate immune signaling platforms.
• Pyroptosis, a programmed cell death, is induced by inflammasomes.
• The role of reactive oxygen species (ROS) in inflammasome regulation is not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which ROS control inflammasome-mediated pyroptosis.
• To identify direct targets of ROS within the pyroptosis pathway.

Main Methods:

• Investigated the interaction between ROS and gasdermin D (GSDMD).
• Utilized exogenous and endogenous ROS sources and ROS-inducing stimuli.
• Employed mutagenesis studies focusing on cysteine residues in GSDMD, specifically C192.

Main Results:

• Gasdermin D (GSDMD) is identified as a direct target of ROS.
• ROS promote the oligomerization of cleaved GSDMD, leading to membrane pore formation and pyroptosis.
• Oxidative modification of cysteine 192 (C192) in GSDMD is essential for ROS-mediated enhancement of its activity.
• GSDMD mutants lacking C192 exhibit impaired pyroptosis induction in macrophages.

Conclusions:

• Cellular redox state critically influences GSDMD activity and pyroptosis.
• ROS act as key regulators of GSDMD-dependent cell death.
• Cysteine 192 is the sole cysteine residue mediating ROS responsiveness in GSDMD.