Neddylation pathway regulates the proliferation and survival of macrophages

Lihui Li, Binghong Liu, Tiangeng Dong, Hyuk Woo Lee, Jinha Yu, Yijie Zheng, Haifeng Gao, Yan Zhang, Yiwei Chu, Guangwei Liu, Weixin Niu, Shimin Zheng, Lak Shin Jeong, Lijun Jia

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Neddylation is a new type of protein post-translational modification which adds the ubiquitin-like molecule Nedd8 to target proteins. The well-identified targets of neddylation are cullins, which serve as essential components of Cullin-RING E3 ligases (CRL). It is reported that inhibition of neddylation repressed NF-κB-mediated proinflammatory cytokine production in macrophages. However, the role of neddylation in the proliferation and survival of macrophages has not been well defined. Here we report that partial inactivation of the neddylation pathway by a specific Nedd8-activating enzyme E1 (NAE) inhibitor MLN4924 reduced LPS-induced production of the proinflammatory cytokines TNF-α and IL-6 without obvious impairment of cell viability. However, persistent and severe inactivation of neddylation by MLN4924 significantly inhibited cell proliferation by inducing G2 phase cell-cycle arrest and further triggered cell death by inducing apoptosis in RAW264.7 macrophages. Mechanistic analysis revealed that inactivation of neddylation blocked cullin neddylation, inhibited CRL E3 ligase activity, and thus led to the accumulation of CRL substrates, resulting in cell-cycle arrest, DNA damage response and apoptosis. The findings revealed that neddylation serves as an important signaling pathway regulating the proliferation and survival of macrophages.

Original languageEnglish
Pages (from-to)494-498
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume432
Issue number3
DOIs
StatePublished - 15 Mar 2013

Keywords

  • Cullin-RING E3 ligase
  • Macrophages
  • MLN4924
  • Neddylation
  • Proliferation and survival

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