NEDD4L-mediated Gasdermin D and E ubiquitination regulates cell death and tissue injury
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(Published version)
Date
2025
Authors
Shah, S.S.
Manning, J.A.
Lim, Y.
Sinha, D.
Murthy, A.M.V.
Ganesan, R.
Robinson, N.
Alnemri, E.S.
Masters, S.L.
Vince, J.E.
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Journal article
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Cell Death and Differentiation, online, 2025; online(4):1-18
Statement of Responsibility
Sonia S. Shah, Jantina A. Manning, Yoon Lim, Diva Sinha, Ambika Mosale Venkatesh Murthy, Raja Ganesan, Nirmal Robinson, Emad S. Alnemri, Seth L. Masters, James E. Vince, Sharad Kumar
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Abstract
The membrane pore-forming gasdermin (GSDM) proteins are essential executors of pyroptosis. The GSDM family members GSDMD and GSDME can also target mitochondrial membranes, driving apoptosis. Here, we identify the ubiquitin ligase NEDD4L as a key regulator of GSDMD and GSDME, two GSDMs involved in cell death. NEDD4L ubiquitinates both these proteins to control their stability and intracellular expression levels. Knockout of mouse Nedd4l (also called Nedd4-2) results in lung and kidney damage with perinatal lethality within three weeks of birth. These mice demonstrated elevated GSDMD in alveolar epithelia and increased GSDME in kidney tubular epithelia, suggesting tissue-specific regulation by NEDD4L. Renal tubule-specific Nedd4l knockout mice showed GSDM activation, tubular cell death and reduced kidney function after high sodium diet. NEDD4L-deficient cells showed increased GSDM activation, IL-1β release and were significantly more susceptible to cell death induced by NLRP3 agonists, cytotoxic agents, and bacterial infection. These results demonstrate that NEDD4L regulates GSDMD and GSDME functions by preventing their accumulation and reveals an unexplored link between GSDM stability and cell death.
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.