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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3503-8. doi: 10.1073/pnas.1525580113. Epub 2016 Mar 14.

Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function.

Author information

1
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
2
National Institute of Biological Sciences, Beijing 102206, China;
3
Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195;
4
Department of Pharmacology and Molecular Science, Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
5
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511;
6
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511; Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 ssnyder@jhmi.edu raofeng@nibs.ac.cn.
7
National Institute of Biological Sciences, Beijing 102206, China; ssnyder@jhmi.edu raofeng@nibs.ac.cn.

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.

KEYWORDS:

COP9 signalosome; CRL; IP5K; cullin RING E3 ligases; inositol hexakisphosphate

PMID:
26976604
PMCID:
PMC4822622
DOI:
10.1073/pnas.1525580113
[Indexed for MEDLINE]
Free PMC Article

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