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Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway

Charles L Evavold1, Iva Hafner-Bratkovič2, Pascal Devant1

  • 1Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Cell
|July 21, 2021
PubMed

Insights

The Ragulator-Rag complex is essential for gasdermin D (GSDMD) pore formation during pyroptosis, a cell death process. This discovery links immune regulation and cellular metabolism.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Pyroptosis is a programmed cell death pathway crucial for immunity.
  • Inflammasomes and gasdermin D (GSDMD) are key mediators of pyroptosis.
  • While GSDMD cleavage is well-studied, the mechanisms of its downstream pore formation remain unclear.

Purpose of the Study:

  • To identify novel proteins required for gasdermin D (GSDMD) pore formation.
  • To elucidate the molecular mechanisms governing GSDMD-mediated pyroptosis.

Main Methods:

  • Forward genetic screen in macrophages.
  • Biochemical assays to assess GSDMD cleavage, oligomerization, and pore formation.
  • Analysis of reactive oxygen species (ROS) production.

Main Results:

  • The Ragulator-Rag complex was identified as essential for GSDMD pore formation and pyroptosis.
  • Ragulator-Rag is not involved in GSDMD cleavage but promotes its oligomerization at the plasma membrane.
  • Mitochondrial poisons that increase reactive oxygen species (ROS) can rescue GSDMD pore formation defects.

Conclusions:

  • The Ragulator-Rag complex plays a critical, previously unrecognized role in GSDMD pore formation.
  • Reactive oxygen species (ROS) are important regulators of GSDMD pore assembly downstream of cleavage.
  • This study reveals a novel connection between immune signaling pathways and metabolic regulation.
Keywords:
gasdermin Dinflammasomesinflammationinnate immunitymacrophagesmtorc1pyroptosisragulatorreactive oxygen species

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