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Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4

ABSTRACT: In this study, we elucidated the mode of action of a class of drugs as NEDD4 inhibitors. These first-in-class NEDD4 inhibitors demonstrated exceptional specificity and selectivity, leaving the other family members unaffected.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Lung Cancer

SUBMITTER: Elena Maspero

LAB HEAD: Simona Polo

PROVIDER: PXD062777 | Pride | 2025-05-29

REPOSITORIES: Pride

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			Action	DRS
	EM_SP_01_01.raw	Raw
	EM_SP_01_01_r.raw	Raw
	EM_SP_01_02.raw	Raw
	EM_SP_01_02_r.raw	Raw
	EM_SP_01_03.raw	Raw

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RNA-sequencing of Nedd4+/+ and Nedd4-/- mouse splenic B cells

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

RNA-sequencing of Nedd4+/+ and Nedd4-/- mouse splenic B cells

2013-08-07 | GSE49027 | GEO

Gene expression changes in NCU10K cells lacking Nedd4

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

H3K9ac occupancy of Nedd4- or control-knockdown Hep3B cells

Project description:H3 Nedd4

2017-06-12 | GSE66340 | GEO

Gene expression profiling of Nedd4- or control-knockdown Hep3B cells

Project description:Gene expression profiling of Nedd4 or control knockdown Hep3B cells

2017-06-12 | GSE66341 | GEO

Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins

Project description:Nedd4-2 E3 ligase regulates Na+ homeostasis by ubiquitinating various channels and membrane transporters, including the epithelial sodium channel ENaC. In turn, Nedd4-2 dysregulation leads to various conditions, including electrolytic imbalance, respiratory distress, hypertension, and kidney diseases. However, Nedd4-2 regulation remains mostly unclear. The present study aims at elucidating Nedd4-2 regulation by structurally characterizing Nedd4-2 and its complexes using several biophysical techniques. Our cryo-EM reconstruction showed that the C2 domain blocks the E2-binding surface of the HECT domain. This blockage, ubiquitin-binding exosite masking by the WW1 domain, catalytic C922 blockage and HECT domain stabilization provide the structural basis for Nedd4-2 autoinhibition. Furthermore, Ca2+-dependent C2 membrane binding disrupts C2/HECT interactions, but not Ca2+ alone, whereas 14-3-3 protein binds to a flexible region of Nedd4-2 containing the WW2 and WW3 domains, thereby inhibiting its catalytic activity and membrane binding. Overall, our data provide key mechanistic insights into Nedd4-2 regulation toward fostering the development of strategies targeting Nedd4-2 function.

2025-05-12 | PXD058899 | Pride

E3 ubiquitin ligase NEDD4-1 suppresses acetaminophen-induced liver injury in mouse by targeting the degradation of VDAC1

Project description:Acetaminophen (APAP) overdose provokes various degrees of liver injury, whose pathogenesis involves multiple pathological events, such as mitochondrial damage and necrosis. E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) plays vital roles in regulating a wide spectrum of physiological processes, and has been implicated in the pathogenesis of numerous liver disease. However, studies about the regulation of NEDD4-1 on APAP-induced liver injury (AILI) is still deficient. Thus, the aim of this study is to determine whether and how NEDD4-1 plays a role in AILI. Thus, we performed transcriptomic studies comparing liver samples of APAP-treated Flox or APAP-treated hepatocyte-specific Nedd4-1 (HepKO) deficiency mice,

2022-03-29 | GSE199353 | GEO

Role of NEDD4 E3s in CD4+ T cell activation

Project description:Itch and WWP2 belongs to NEDD4 E3 family, and highly share the structural homology. However it remains elusive whether there are redundant or distinct roles in helper CD4+ T cell differentiation. Here we performed RNA seq analysis using WT, single and double knockout CD4+ T cells, and demonstrated the cooperative effect of the two E3s on Th2 differentiation.

2018-05-24 | GSE114021 | GEO

Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity

Project description:Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2 and an isobaric labeling approach for quantitative comparison of the synaptic membrane proteome, we identified astrocytic channel proteins inwardly rectifying potassium channel 4.1 (Kir4.1) and Connexin43 as upregulated in ubiquitin ligase knockout mice and thus as candidate Nedd4-2 substrates. Kir4.1 and Connexin43 were confirmed as Nedd4-2 substrates by independent methods and their functional role in astrocytes as to modulation of neuronal network activity was established.

2023-11-28 | PXD046450 | Pride

Transcriptomics analysis of sciatic nerves with conditional deletion of Nedd4 in the Schwann cell (SC) lineage during development.

Project description:RNA sequencing was performed to evaluate the transcriptome of sciatic nerves extracted from mice with conditional deletion of Nedd4 in the SC-lineage during development.

2024-11-08 | GSE217272 | GEO

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