The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy
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PROVIDER: PRJNA1227595 | ENA |
REPOSITORIES: ENA
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Project description:The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy
| PRJNA1227594 | ENA
Project description: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 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.
| S-EPMC11920435 | biostudies-literature
Project description:Data deposited contain results from proximity-dependent biotinylation LC-MS (BioID) experiments in which T-REx Flp-In HEK293 cells express NEDD4 protein versions in-frame with biotin carboxylase miniTurbo.
2024-01-09 | MSV000093801 | MassIVE
Project description:Programmed mutagenesis of the immunoglobulin locus of B-lymphocytes during class switch recombination and somatic hypermutation requires RNA polymerase II (RNA polII) transcription complex dependent targeting of the DNA mutator, Activation Induced cytidine Deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism and this activity is stimulated by the RNA polII stalling co-factor Spt5 and the eleven-subunit cellular non-coding RNA 3’-5’ exonucleolytic processing complex, RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event leading to generation of 3’-end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. Using highthrough-out RNA sequencing technology, we find that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes. Moreover, we find that Nedd4-deficient B cells are inefficient in undergoing class switch recombination. Taken together, our study links non-coding RNA processing following RNA polymerase II pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of non-coding RNA that are generated by stalled RNA polII genome-wide. Splenic B cells from Nedd4+/+ and Nedd4-/- B cells fetal liver chimeric mice were were stimulated in culture for IgG1 CSR. Total RNA was isolated and evaluated with whole genome RNA-seq
2013-08-07 | E-GEOD-49027 | biostudies-arrayexpress
Project description:Nedd4 is an E3 ubiquitin ligase that has essential roles in neural crest cell development. This study aimed to detect the gene expression changes induced by removing Nedd4 in the neural crest cell line, NCU10K, to define the molecular pathways regulated by Nedd4.
2022-03-02 | GSE197631 | GEO
Project description:Programmed mutagenesis of the immunoglobulin locus of B-lymphocytes during class switch recombination and somatic hypermutation requires RNA polymerase II (RNA polII) transcription complex dependent targeting of the DNA mutator, Activation Induced cytidine Deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism and this activity is stimulated by the RNA polII stalling co-factor Spt5 and the eleven-subunit cellular non-coding RNA 3’-5’ exonucleolytic processing complex, RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event leading to generation of 3’-end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. Using highthrough-out RNA sequencing technology, we find that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes. Moreover, we find that Nedd4-deficient B cells are inefficient in undergoing class switch recombination. Taken together, our study links non-coding RNA processing following RNA polymerase II pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of non-coding RNA that are generated by stalled RNA polII genome-wide.
2013-08-07 | GSE49027 | GEO
Project description:H3 Nedd4
2017-06-12 | GSE66340 | GEO
Project description:Gene expression profiling of Nedd4 or control knockdown Hep3B cells
2017-06-12 | GSE66341 | GEO
Project description:Drosophila melanogaster Nedd4, Nedd4, is differentially expressed in 9 experiment(s);
| FBgn0259174 | ExpressionAtlas
Project description:Drosophila melanogaster Nedd4, Nedd4, is expressed in 4 baseline experiment(s);
| FBgn0259174 | ExpressionAtlas