ArticlePLoS pathogens2015
E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 118 citations in OpenAlex.
- Interferon-induced transmembrane proteins in cancer and virus biology: a membrane perspective.mBio · 2026Review
- MYCT1-IFITM2/3 interaction links endothelial endolysosomal trafficking to white adipose tissue expansion.The Journal of experimental medicine · 2026Article
- E3 ubiquitin ligase NEDD4 inhibits PEDV infection through ubiquitination and degradation of the viral primase NSP8.Journal of virology · 2026Article
- IFITM3 deficiency drives SARS-CoV-2 adaptation while preserving variant-specific traits.Nature communications · 2026Article
- Interferon-induced transmembrane proteins: membrane gatekeepers of fusion and infection.Frontiers in cellular and infection microbiology · 2026Review
- IFITM3-deficient mice as a model for testing influenza virus vaccines via the intramuscular route.Vaccine · 2025Article
- Review
- Attenuation of IFITM proteins' antiviral activity through sequestration into intraluminal vesicles of late endosomes.Frontiers in immunology · 2025Article
- Review
- Host Innate Antiviral Response to Influenza A Virus Infection: From Viral Sensing to Antagonism and Escape.Pathogens (Basel, Switzerland) · 2024Review
- Role of Nedd4L in Macrophage Pro-Inflammatory Polarization Induced by Influenza A Virus and Lipopolysaccharide Stimulation.Microorganisms · 2024Article
- Silencing RNA-Mediated Knockdown of IFITM3 Enhances Senecavirus A Replication.Pathogens (Basel, Switzerland) · 2024Article
- Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs.Pathogens (Basel, Switzerland) · 2024Review
- A Proteomics-Based Approach Identifies the NEDD4 Adaptor NDFIP2 as an Important Regulator of Ifitm3 Levels.Viruses · 2023Article
- Cyclosporines Antagonize the Antiviral Activity of IFITMProteins by Redistributing Them toward the Golgi Apparatus.Biomolecules · 2023Article
- Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice.EMBO reports · 2023Article
- Caveats of Using Overexpression Approaches to Screen Cellular Host IFITM Proteins for Antiviral Activity.Pathogens (Basel, Switzerland) · 2023Article
- Article
- Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2.The Journal of clinical investigation · 2022Article
- Transcriptomic response to ISAV infection in the gills, head kidney and spleen of resistant and susceptible Atlantic salmon.BMC genomics · 2022Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Interferon (IFN)-induced transmembrane protein 3 (IFITM3) is a cell-intrinsic factor that limits influenza virus infections. We previously showed that IFITM3 degradation is increased by its ubiquitination, though the ubiquitin ligase responsible for this modification remained elusive. Here, we demonstrate that the E3 ubiquitin ligase NEDD4 ubiquitinates IFITM3 in cells and in vitro. This IFITM3 ubiquitination is dependent upon the presence of a PPxY motif within IFITM3 and the WW domain-containing region of NEDD4. In NEDD4 knockout mouse embryonic fibroblasts, we observed defective IFITM3 ubiquitination and accumulation of high levels of basal IFITM3 as compared to wild type cells. Heightened IFITM3 levels significantly protected NEDD4 knockout cells from infection by influenza A and B viruses. Similarly, knockdown of NEDD4 in human lung cells resulted in an increase in steady state IFITM3 and a decrease in influenza virus infection, demonstrating a conservation of this NEDD4-dependent IFITM3 regulatory mechanism in mouse and human cells. Consistent with the known association of NEDD4 with lysosomes, we demonstrate for the first time that steady state turnover of IFITM3 occurs through the lysosomal degradation pathway. Overall, this work identifies the enzyme NEDD4 as a new therapeutic target for the prevention of influenza virus infections, and introduces a new paradigm for up-regulating cellular levels of IFITM3 independently of IFN or infection.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.