ArticlePloS one2013
Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 58 citations in OpenAlex.
- Regulation of CFTR stability at the plasma membrane-Mechanisms and therapeutic opportunities in cystic fibrosis.FEBS letters · 2026Review
- MARCH E3 Ligases: Understudied Regulators of Pulmonary Immune Function.Journal of respiratory biology and translational medicine · 2026Article
- Membrane-associated ring-CH-type finger 2 protects against metabolic dysfunction-associated fatty liver disease by targeting fatty acid synthase.Molecular metabolism · 2025Article
- The E3 ubiquitin ligase MARCH2 controls TNF-α mediated inflammation by autoubiquitination.Cell communication and signaling : CCS · 2025Article
- Analysis of transcriptome and metabolome characteristics of blood in yaks at different reproductive stages.Frontiers in veterinary science · 2025Article
- Research progress of deubiquitinating enzymes in cerebral ischemia-reperfusion injury.Frontiers in aging neuroscience · 2025Review
- MARCH2, a T cell specific factor that restricts HIV-1 infection.PLoS pathogens · 2024Article
- Colocalization analysis of 3' UTR alternative polyadenylation quantitative trait loci reveals novel mechanisms underlying associations with lung function.Human molecular genetics · 2024Article
- Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?Cellular and molecular life sciences : CMLS · 2024Review
- MARCH2, a Novel Oncogene-regulated SNAIL E3 Ligase, Suppresses Triple-negative Breast Cancer Metastases.Cancer research communications · 2024Article
- The expression system influences stability, maturation efficiency, and oligomeric properties of the potassium-chloride co-transporter KCC2.Neurochemistry international · 2024Article
- Distinct Molecular Features of NleG Type 3 Secreted Effectors Allow for Different Roles during Citrobacter rodentium Infection in Mice.Infection and immunity · 2023Article
- Targeting the E1 ubiquitin-activating enzyme (UBA1) improves elexacaftor/tezacaftor/ivacaftor efficacy towards F508del and rare misfolded CFTR mutants.Cellular and molecular life sciences : CMLS · 2022Article
- Revisiting CFTR Interactions: Old Partners and New Players.International journal of molecular sciences · 2021Review
- Analysis of multiple gene co-expression networks to discover interactions favoring CFTR biogenesis and ΔF508-CFTR rescue.BMC medical genomics · 2021Article
- Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response.The Journal of biological chemistry · 2021Review
- MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes.Nature communications · 2021Article
- MAGI-1 PDZ2 Domain Blockade Averts Adenovirus Infection via Enhanced Proteolysis of the Apical Coxsackievirus and Adenovirus Receptor.Journal of virology · 2021Article
- Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2.The EMBO journal · 2020Article
- Review
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Golgi-localized cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand (CAL) and syntaxin 6 (STX6) regulate the abundance of mature, post-ER CFTR by forming a CAL/STX6/CFTR complex (CAL complex) that promotes CFTR degradation in lysosomes. However, the molecular mechanism underlying this degradation is unknown. Here we investigated the interaction of a Golgi-localized, membrane-associated RING-CH E3 ubiquitin ligase, MARCH2, with the CAL complex and the consequent binding, ubiquitination, and degradation of mature CFTR. We found that MARCH2 not only co-immunoprecipitated and co-localized with CAL and STX6, but its binding to CAL was also enhanced by STX6, suggesting a synergistic interaction. In vivo ubiquitination assays demonstrated the ubiquitination of CFTR by MARCH2, and overexpression of MARCH2, like that of CAL and STX6, led to a dose-dependent degradation of mature CFTR that was blocked by bafilomycin A1 treatment. A catalytically dead MARCH2 RING mutant was unable to promote CFTR degradation. In addition, MARCH2 had no effect on a CFTR mutant lacking the PDZ motif, suggesting that binding to the PDZ domain of CAL is required for MARCH2-mediated degradation of CFTR. Indeed, silencing of endogenous CAL ablated the effect of MARCH2 on CFTR. Consistent with its Golgi localization, MARCH2 had no effect on ER-localized ΔF508-CFTR. Finally, siRNA-mediated silencing of endogenous MARCH2 in the CF epithelial cell line CFBE-CFTR increased the abundance of mature CFTR. Taken together, these data suggest that the recruitment of the E3 ubiquitin ligase MARCH2 to the CAL complex and subsequent ubiquitination of CFTR are responsible for the CAL-mediated lysosomal degradation of mature CFTR.
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Registered trials
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.