The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy

The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW<sub>(n)</sub>-HECT domains, regulates protein trafficking. We recently described a primate-specific Nedd4-1 splice isoform with an extended N-terminus replacing the C2 domain, called Nedd4-1(NE). Here, we show that while canonical Nedd4-1 is primarily localized to the cytosol, Nedd4-1(NE) localizes to late endosomes. This localization is mediated by the NE region, is dependent on amino acid availability, is independent of mTORC1, and is inhibited by the autophagy inducer IKKβ. We further demonstrate that VPS16B, which regulates late endosome to lysosome maturation, is a unique Nedd4-1(NE) substrate that co-localizes with Nedd4-1(NE) in the presence of nutrients. Importantly, a potentially pathogenic homozygous variant identified in the NE region (E70Q) of a patient with lymphangiectasia and protein-losing enteropathy leads to reduced VPS16B ubiquitination by Nedd4-1(NE). Finally, we report that Nedd4-1(NE) inhibits autophagy, likely by disrupting late endosome to autophagosome maturation. This work identified an mTORC1-independent, IKK-driven mechanism to regulate Nedd4-1(NE) localization to late endosomes in primates in response to nutrient availability, and uncovered suppression of autophagy by this ubiquitin ligase.

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Publication Details

Journal
Nature Communications
Published
2025-03-18
DOI
https://doi.org/10.1038/s41467-025-57944-x
Citations
1
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
1.15

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article

The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy

Walter H.A. Kahr, John H. Brumell, Helen C. Su, Neil Warner et al.
1 citations
Nature Communications
Cellular transport and secretion
1.15
article

The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy

Walter H.A. Kahr, John H. Brumell, Helen C. Su, Neil Warner, Daniela Rotin, Audrey Astori, Aleixo M. Muise, Brian Raught, Amulya Priya, Avinash K. Persaud, Andrew M. Sydor, Soyar Sari, Michael J. Lenardo, George Kefalas, Yue Zhang, Jing Li, Helen H.Y. Yao
article en
1 citations

Abstract

The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW<sub>(n)</sub>-HECT domains, regulates protein trafficking. We recently described a primate-specific Nedd4-1 splice isoform with an extended N-terminus replacing the C2 domain, called Nedd4-1(NE). Here, we show that while canonical Nedd4-1 is primarily localized to the cytosol, Nedd4-1(NE) localizes to late endosomes. This localization is mediated by the NE region, is dependent on amino acid availability, is independent of mTORC1, and is inhibited by the autophagy inducer IKKβ. We further demonstrate that VPS16B, which regulates late endosome to lysosome maturation, is a unique Nedd4-1(NE) substrate that co-localizes with Nedd4-1(NE) in the presence of nutrients. Importantly, a potentially pathogenic homozygous variant identified in the NE region (E70Q) of a patient with lymphangiectasia and protein-losing enteropathy leads to reduced VPS16B ubiquitination by Nedd4-1(NE). Finally, we report that Nedd4-1(NE) inhibits autophagy, likely by disrupting late endosome to autophagosome maturation. This work identified an mTORC1-independent, IKK-driven mechanism to regulate Nedd4-1(NE) localization to late endosomes in primates in response to nutrient availability, and uncovered suppression of autophagy by this ubiquitin ligase.

Nature CommunicationsVol. 16(1)
National Institutes of Health (US), University Health Network (CA), University of Toronto (CA), Hospital for Sick Children (CA), Princess Margaret Cancer Centre (CA), National Institute of Allergy and Infectious Diseases (US), SickKids Foundation (CA), Gazi University (TR)
Canadian Institutes of Health Research, CIHR Skin Research Training Centre
Zero hunger
Openalex Percentile: Top 27%
Cellular transport and secretion
1.15
DOIOpen Access PDFOpenAlex
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