ArticleProceedings of the National Academy of Sciences of the United States of America2023
Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 28 citations in OpenAlex.
- Fine-Tuned Regulation of mRNA Translation and Transport by STAU2 Condensate Facilitates Neuronal Development and Plasticity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dual-targeted engineered mesenchymal stem cell-derived extracellular vesicles delivering Nedd4 attenuate renal fibrosis in diabetic kidney disease.Materials today. Bio · 2026Article
- The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.Toxicological research · 2026Review
- Nanobody-based bioPROTAC for viral protein degradation provides an antiviral strategy for porcine arterivirus.Journal of nanobiotechnology · 2026Article
- Liquid-liquid phase separation couples MKRN2-mediated ubiquitination of CSDE1 with neurodevelopmental disorders.Frontiers in cellular neuroscience · 2026Article
- SRSF9 mediates oncogenic RNA splicing of SLC37A4 via liquid-liquid phase separation to promote oral cancer progression.Journal of advanced research · 2026Article
- Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression.Nature structural & molecular biology · 2025Article
- Deep learning-enhanced clustering and classification of protein molecule tertiary structures using weighted distance matrices.Briefings in bioinformatics · 2025Article
- Targeting redox-sensitive MBD2-NuRD condensate in cancer cells.Nature cell biology · 2025Article
- Phase separation of the poplar microtubule-associated protein PagPCaP1a aids microtubule depolymerization in response to high salt.Science advances · 2025Article
- Protein quality control machinery: regulators of condensate architecture and functionality.Trends in biochemical sciences · 2025Review
- Ubiquitination in lipid metabolism reprogramming: implications for pediatric solid tumors.Frontiers in immunology · 2025Review
- Liquid-liquid phase separation: an emerging perspective on the tumorigenesis, progression, and treatment of tumors.Frontiers in immunology · 2025Review
- Single-cell and multi-omics analysis identifies TRIM9 as a key ubiquitination regulator in pancreatic cancer.Frontiers in immunology · 2025Article
- Liquid-liquid phase separation in cell physiology and cancer biology: recent advances and therapeutic implications.Frontiers in oncology · 2025Review
- Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.The Journal of cell biology · 2024Article
- Article
- Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.bioRxiv : the preprint server for biology · 2024Article
- Phase separation promotes the activity of HECT E3 ligases-A word of caution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism is highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome-related protein Spartin activates and recruits HECT-type E3 Itch to lipid droplets (LDs) to regulate their turnover. In this study, we find that Spartin promotes the formation of Itch condensates independent of LDs. Spartin activates Itch through its multiple PPAY-motif platform generated by self-oligomerization, which targets the WW12 domains of Itch and releases the autoinhibition of the ligase. Spartin-induced activation and subsequent autoubiquitination of Itch lead to liquid-liquid phase separation (LLPS) of the poly-, but not oligo-, ubiquitinated Itch together with Spartin and E2 both in vitro and in living cells. LLPS-mediated condensation of the reaction components further accelerates the generation of polyubiquitin chains, thus forming a positive feedback loop. Such Itch-Spartin condensates actively promote the autophagy-dependent turnover of LDs. Moreover, we show that the catalytic HECT domain of Itch is sufficient to interact and phase separate with poly-, but not oligo-ubiquitin chains. HECT domains from other HECT E3 ligases also exhibit LLPS-mediated the promotion of ligase activity. Therefore, LLPS and ubiquitination are mutually interdependent and LLPS promotes the ligase activity of the HECT family E3 ligases.
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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.