ArticleThe Journal of biological chemistry2018
Phosphorylation of the E3 ubiquitin protein ligase ITCH diminishes binding to its cognate E2 ubiquitin ligase.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- TRIM47-mediated Ubiquitination of p53 Controls Proliferative Progression and Stress Adaptation in Glioblastoma.International journal of biological sciences · 2026Article
- The role of HECT-type E3 ubiquitin ligases in inflammation.Frontiers in immunology · 2026Review
- Metabolic and post-translational modifications in sepsis-associated immune dysfunction: a conceptual framework.Frontiers in immunology · 2026Review
- PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Phosphoproteomic Analysis Reveals Impairment of Rice Germination by Chloramphenicol.Plants (Basel, Switzerland) · 2025Article
- Natural lung-tropic TJournal for immunotherapy of cancer · 2024Article
- Oxidative Stress Promotes Liver Cancer Metastasis via RNF25-Mediated E-Cadherin Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Post-translational modifications in sepsis-induced organ dysfunction: mechanisms and implications.Frontiers in immunology · 2024Review
- Phosphoproteome analyses pinpoint the F-box protein SLOW MOTION as a regulator of warm temperature-mediated hypocotyl growth in Arabidopsis.The New phytologist · 2024Article
- β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination.The Journal of biological chemistry · 2023Article
- Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road.Biomolecules · 2022Review
- Localization of the ubiquitin ligase Dma1 to the fission yeast contractile ring is modulated by phosphorylation.FEBS letters · 2021Article
- ITCH as a potential therapeutic target in human cancers.Seminars in cancer biology · 2020Review
- Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration.Cell death & disease · 2020Article
- Transcriptome Profiling of Bovine Macrophages Infected byFrontiers in immunology · 2019Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Heightened and extended inflammation underlies the pathogenesis of many disorders, including inflammatory bowel disease, sepsis, and inflammatory arthritis. Ubiquitin networks help dictate the strength and duration of inflammatory signaling. In innate immunity, the itchy E3 ubiquitin protein ligase (ITCH)-A20 ubiquitin-editing complex inhibits receptor-interacting Ser/Thr kinase (RIPK) activation by removing Lys-63-linked polyubiquitinated chains from key proteins in the nuclear factor kappa B (NF-κB) signaling pathway. The complex then attaches polyubiquitinated chains to these proteins to target them for lysosomal or proteasomal destruction. ITCH is phosphorylated and thereby inhibited by inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) to fine-tune the inflammatory response to the strength of the offending signal. However, the biochemical mechanism by which E3 ubiquitination is impaired by IKK-driven phosphorylation remains unclear. Here, we report that this phosphorylation impedes ITCH binding to its cognate E2 ubiquitin ligase, UbcH7. Using CRISPR-Cas9 genetic knockout to mimic the ITCH-UbcH7-inhibited state, we further show that genetic UbcH7 deficiency phenocopies ITCH phosphorylation in regulating RIPK2 ubiquitination. We conclude that phosphorylation can disrupt the binding of an E3 ubiquitin ligase to an E2-conjugating enzyme, leading to prolonged inflammatory signaling. To our knowledge, this is the first report of E3 ubiquitin ligase phosphorylation inhibiting E3 ligase activity by impairing E2-E3 complex formation.
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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.