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 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

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Cullin Proteins
Phytic Acid
Ubiquitin-Protein Ligases
Polyphosphates
Ubiquitination
Inositol
Proteome
Static Electricity
Adhesives
Phosphotransferases
Cell Proliferation
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. / Scherer, Paul C.; Ding, Yan; Liu, Zhiqing; Xu, Jing; Mao, Haibin; Barrow, James; Wei, Ning; Zheng, Ning; Snyder, Solomon H; Rao, Feng.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 13, 29.03.2016, p. 3503-3508.

Research output: Contribution to journalArticle

Scherer, Paul C. ; Ding, Yan ; Liu, Zhiqing ; Xu, Jing ; Mao, Haibin ; Barrow, James ; Wei, Ning ; Zheng, Ning ; Snyder, Solomon H ; Rao, Feng. / Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 13. pp. 3503-3508.
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AU - Scherer, Paul C.

AU - Ding, Yan

AU - Liu, Zhiqing

AU - Xu, Jing

AU - Mao, Haibin

AU - Barrow, James

AU - Wei, Ning

AU - Zheng, Ning

AU - Snyder, Solomon H

AU - Rao, Feng

PY - 2016/3/29

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AB - 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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KW - Hexakisphosphate

KW - Inosito

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