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

Paul C. Scherer, Yan Ding, Zhiqing Liu, Jing Xu, Haibin Mao, James C. Barrow, Ning Wei, Ning Zheng, Solomon H. Snyder, Feng Rao

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3503-3508
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number13
DOIs
StatePublished - Mar 29 2016

Keywords

  • COP9 signalosome IP5K
  • CRL
  • Cullin RING E3 ligases
  • Hexakisphosphate
  • Inosito

ASJC Scopus subject areas

  • General

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