title: Neddylation pathway regulates the proliferation and survival of macrophages.
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.
authors: College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
authors: Lihui
authors: L
authors: Li
authors: Binghong
authors: B
authors: Liu
authors: Tiangeng
authors: T
authors: Dong
authors: Hyuk Woo
authors: HW
authors: Lee
authors: Jinha
authors: J
authors: Yu
authors: Yijie
authors: Y
authors: Zheng
authors: Haifeng
authors: H
authors: Gao
authors: Yan
authors: Y
authors: Zhang
authors: Yiwei
authors: Y
authors: Chu
authors: Guangwei
authors: G
authors: Liu
authors: Weixin
authors: W
authors: Niu
authors: Shimin
authors: S
authors: Zheng
authors: Lak Shin
authors: LS
authors: Jeong
authors: Lijun
authors: L
authors: Jia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D003517:Cyclopentanes / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D016207:Cytokines; C583290:Nedd8-activating enzyme E1 protein, mouse; D011743:Pyrimidines; D044767:Ubiquitin-Protein Ligases; D044764:Ubiquitin-Activating Enzymes; C539933:pevonedistat