Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments

Area of Science:

• Cellular biology
• Immunology
• Biochemistry

Background:

• Gasdermin (GSDM) proteins are key executioners of pyroptosis, a pro-inflammatory programmed cell death.
• GSDM-mediated plasma membrane (PM) pore formation is crucial for cytokine secretion and ion flux during pyroptosis.
• Emerging evidence indicates GSDMs interact with intracellular organelle membranes, suggesting roles beyond pyroptosis.

Purpose of the Study:

• To review the diverse mechanisms of GSDM protein association with intracellular organelle membranes.
• To discuss the physiological and pathological consequences of GSDM-induced alterations in organelle membrane integrity.
• To highlight novel signaling pathways regulated by GSDMs independent of plasma membrane perforation.

Main Methods:

• Literature review of studies investigating GSDM protein functions.
• Analysis of research on GSDM interactions with mitochondria, lysosomes, endoplasmic reticulum (ER), and nuclear membranes.
• Synthesis of findings on GSDM-mediated membrane permeabilization and its signaling outcomes.

Main Results:

• GSDMs associate with and modify membranes of various organelles, including mitochondria, lysosomes, ER, and the nucleus.
• These intracellular GSDM activities can trigger signaling pathways distinct from pyroptosis.
• GSDM-induced membrane alterations contribute to both normal cellular processes and pathological conditions.

Conclusions:

• Gasdermin proteins possess multifaceted roles in cellular regulation extending beyond pyroptosis.
• Understanding GSDM-organelle interactions is critical for elucidating novel cell death and signaling pathways.
• Targeting GSDM-membrane interactions may offer therapeutic strategies for inflammatory and other diseases.