Palmitoylation Activates Gasdermin D for Pyroptosis and Cytokine Secretion Downstream of Inflammasome Activation

Core Concepts

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.

Abstract

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.

Stats

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.

Quotes

"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."

Key Insights Distilled From

ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D - Nature

by Gang Du,Liam... at www.nature.com 04-10-2024

https://www.nature.com/articles/s41586-024-07373-5

Deeper Inquiries

How might the regulation of GSDMD palmitoylation be exploited for therapeutic interventions targeting inflammasome-mediated diseases?

The regulation of GSDMD palmitoylation presents a promising avenue for therapeutic interventions in inflammasome-mediated diseases. By targeting the enzymes responsible for palmitoylation, such as zDHHC5 and zDHHC9, it may be possible to modulate the activation of GSDMD and subsequently inhibit pyroptosis and cytokine release. Small molecules or inhibitors that specifically target these palmitoyltransferases could be developed to regulate the palmitoylation status of GSDMD, thereby controlling its pore-forming activity. Additionally, strategies aimed at modulating ROS levels, which enhance GSDMD palmitoylation, could also be explored for therapeutic purposes. Overall, targeting the palmitoylation of GSDMD could offer a novel approach to treating inflammasome-mediated diseases.

What are the potential physiological or pathological conditions that could lead to increased ROS production and subsequent GSDMD palmitoylation and activation?

Several physiological and pathological conditions can lead to increased ROS production, which in turn can enhance GSDMD palmitoylation and activation. Inflammatory processes, such as those triggered by infections or tissue damage, often result in the activation of immune cells that produce ROS as part of their defense mechanisms. Chronic inflammatory conditions, metabolic disorders, and ischemia-reperfusion injuries are examples of pathological conditions associated with elevated ROS levels. Additionally, environmental factors like exposure to pollutants or toxins can also induce ROS generation. These conditions create a pro-oxidative environment that promotes GSDMD palmitoylation and activation, leading to pyroptosis and cytokine release.

What other cellular processes or signaling pathways might be influenced by the palmitoylation of the other human gasdermin family members?

The palmitoylation of other human gasdermin family members could potentially influence various cellular processes and signaling pathways beyond pyroptosis. Palmitoylation is known to regulate protein localization, stability, and interactions with other molecules, suggesting that it may impact the functions of gasdermins in diverse cellular contexts. For instance, palmitoylation of gasdermins could modulate their ability to interact with membrane components, affecting membrane integrity and cellular homeostasis. Furthermore, palmitoylation-mediated changes in protein-protein interactions may influence intracellular signaling cascades involved in inflammation, cell death, and immune responses. Understanding the broader implications of gasdermin palmitoylation on cellular processes could reveal novel roles for these proteins in health and disease.