ArticleProceedings of the National Academy of Sciences of the United States of America2016
Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- Arabidopsis inositol polyphosphate kinase activities regulate COP9 deneddylation functions in phosphate homeostasis.Journal of integrative plant biology · 2026Article
- Meis1 isoform diversity orchestrates neural progenitor differentiation by regulating ATOH1 degradation at distinct subcellular compartments.PLoS biology · 2026Article
- Proteome-wide quantification of inositol pyrophosphate-protein interactions.Nature communications · 2026Article
- Targeting IPNature communications · 2026Article
- Structural basis of CSN-mediated SCF deneddylation.Nature communications · 2026Article
- Versatile roles of inositol hexakisphosphate in the ubiquitin-proteasome system.Essays in biochemistry · 2025Review
- Interaction of OsCSN2 with OsCULs Under Red and Far-Red Light Regulates Stem and Coleoptile Growth in Rice.Plants (Basel, Switzerland) · 2025Article
- CSN-CRL Complexes: New Regulators of Adipogenesis.Biomolecules · 2025Review
- Multiple inositol phosphate species enhance stability of active mTOR.bioRxiv : the preprint server for biology · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Structural and functional basis of inositol hexaphosphate stimulation of NHEJ through stabilization of Ku-XLF interaction.Nucleic acids research · 2023Article
- Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6.Nature communications · 2022Article
- 5-IPNature metabolism · 2021Article
- Inositol polyphosphate-protein interactions: Implications for microbial pathogenicity.Cellular microbiology · 2021Review
- IPNature communications · 2021Article
- CRL4AOncogene · 2021Article
- Signalling Properties of Inositol Polyphosphates.Molecules (Basel, Switzerland) · 2020Review
- Role of Inositols and Inositol Phosphates in Energy Metabolism.Molecules (Basel, Switzerland) · 2020Review
- Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate-mediated regulation of cullin-RING ligase and sensitize cancer cells to MLN4924/pevonedistat.The Journal of biological chemistry · 2020Article
- Regulation of Cullin-RING E3 ligase dynamics by Inositol hexakisphosphate.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular "glue," increasing cullin-CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL-CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL-CSN system and are potential targets for cancer therapy in conjunction with MLN4924.
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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.