IKK-Mediated Regulation of the COP9 Signalosome via Phosphorylation of CSN5

Jingzi Zhang, Ruoyu Zhao, Clinton Yu, Christine L.N. Bryant, Kenneth Wu, Zhihong Liu, Yibing Ding, Yue Zhao, Bin Xue, Zhen Qiang Pan, Chaojun Li, Lan Huang, Lei Fang

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The COP9 signalosome (CSN) is an evolutionarily conserved multisubunit protein complex, which controls protein degradation through deneddylation and inactivation of cullin-RING ubiquitin E3 ligases (CRLs). Recently, the CSN complex has been linked to the NF-κB signaling pathway due to its association with the IKK complex. However, how the CSN complex is regulated in this signaling pathway remains unclear. Here, we have carried out biochemical experiments and confirmed the interaction between the CSN and IKK complexes. In addition, we have determined that overexpression of IKKα or IKKβ leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. Interestingly, TNF-α treatment not only enhances the interaction between CSN and IKK but also induces an IKK-dependent phosphorylation of CSN5 at serine 201, linking CSN to TNF-α signaling through IKK. Moreover, TNF-α treatment affects the CSN interaction network globally, especially the associations of CSN with the proteasome complex, eukaryotic translation initiation factor complex, and CRL components. Collectively, our results provide new insights into IKK-mediated regulation of CSN associated with the NF-κB signaling pathway.

Original languageEnglish
Pages (from-to)1119-1130
Number of pages12
JournalJournal of Proteome Research
Volume19
Issue number3
DOIs
StatePublished - 6 Mar 2020

Keywords

  • COP9 signalosome
  • CSN5
  • IKK complex
  • NF-κB signaling pathway
  • TNF-α
  • deneddylation
  • phosphorylation

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