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

ABSTRACT: The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW_(n)-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 t

SUBMITTER: Kefalas G 

PROVIDER: S-EPMC11920435 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature