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NEDD4L-mediated Gasdermin D and E ubiquitination regulates cell death and tissue injury

Sonia S Shah1,2, Jantina A Manning3,4, Yoon Lim3,4

  • 1Centre for Cancer Biology, University of South Australia, Adelaide, SA, 5001, Australia. sonia.shah@unisa.edu.au.

Cell Death and Differentiation
|November 19, 2025
PubMed

Insights

The ubiquitin ligase NEDD4L controls gasdermin (GSDM) protein levels, crucial for cell death pathways like pyroptosis and apoptosis. NEDD4L deficiency leads to GSDM accumulation, causing tissue damage and increased susceptibility to cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Gasdermin (GSDM) proteins are key mediators of pyroptosis and apoptosis.
  • GSDMD and GSDME specifically target mitochondrial membranes, contributing to cell death.
  • Regulation of GSDM protein stability is critical for controlling cell death pathways.

Purpose of the Study:

  • To identify key regulators of GSDMD and GSDME.
  • To investigate the role of the ubiquitin ligase NEDD4L in GSDM regulation.
  • To elucidate the impact of NEDD4L on GSDM-mediated cell death and tissue homeostasis.

Main Methods:

  • Ubiquitination assays to assess NEDD4L's effect on GSDM.
  • Generation and analysis of Nedd4l knockout mouse models (global and tissue-specific).
  • Cellular assays measuring GSDM activation, IL-1β release, and susceptibility to cell death stimuli.

Main Results:

  • NEDD4L directly ubiquitinates GSDMD and GSDME, controlling their stability and expression.
  • Nedd4l knockout mice exhibit perinatal lethality with lung and kidney damage due to elevated GSDM.
  • NEDD4L deficiency in cells increases GSDM activation, IL-1β release, and sensitivity to various cell death triggers.

Conclusions:

  • NEDD4L is a critical negative regulator of GSDMD and GSDME.
  • NEDD4L prevents GSDM accumulation, thereby protecting tissues from excessive cell death.
  • This study reveals a novel mechanism linking ubiquitin ligase activity to GSDM stability and cell death regulation.

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