Neddylation pathway regulates the proliferation and survival of macrophages
| Autor: | Jinha Yu, Lijun Jia, Yiwei Chu, Tiangeng Dong, Yijie Zheng, Yan Zhang, Lak Shin Jeong, Haifeng Gao, Shimin Zheng, Wei-Xin Niu, Guangwei Liu, Lihui Li, Hyuk Woo Lee, Binghong Liu |
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| Rok vydání: | 2013 |
| Předmět: |
Programmed cell death
Cell Survival Ubiquitin-Protein Ligases Biophysics Apoptosis Cyclopentanes Ubiquitin-Activating Enzymes Biochemistry NEDD8 Cell Line Proinflammatory cytokine Mice Animals Molecular Biology Cell Proliferation biology Cell growth Chemistry Macrophages Cell Biology Cell biology Ubiquitin ligase G2 Phase Cell Cycle Checkpoints Pyrimidines biology.protein Cytokines Neddylation Signal transduction Protein Processing Post-Translational Cullin DNA Damage Signal Transduction |
| Zdroj: | Biochemical and Biophysical Research Communications. 432:494-498 |
| ISSN: | 0006-291X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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