1. Academic Validation
  2. Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury

Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury

  • Am J Physiol Lung Cell Mol Physiol. 2017 Jul 1;313(1):L104-L114. doi: 10.1152/ajplung.00410.2016.
Ziyan Zhu 1 Lei Sun 2 Rui Hao 1 Hongchao Jiang 1 Feng Qian 1 3 4 Richard D Ye 1 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
  • 2 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China; sunlei_vicky@sjtu.edu.cn.
  • 3 Research Center for Cancer Precision Medicine, Bengbu Medical College, Bengbu, Anhui Province, People's Republic of China.
  • 4 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, People's Republic of China; and.
  • 5 Institute of Chinese Medical Sciences, University of Macau, Macau Special Administration Region, People's Republic of China.
Abstract

Lung infections are major causes of acute lung injury (ALI), with limited effective treatment available. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an essential adaptor regulating Toll-like receptors (TLRs). We recently identified Cullin-5 (Cul-5) as a prominent component in the regulation of TRAF6 polyubiquitination, but its physiological significance in ALI has not been explored. In this study, we investigated the potential role of Cul-5 in regulating ALI using mice receiving intratracheal instillation of LPS. We observed that Cul-5-deficient mice displayed reduced lung injury compared with wild-type mice as evidenced by histological analysis, alveolar neutrophil infiltration, and lung liquid accumulation. In addition, inflammatory cytokine expression in bronchoalveolar lavage fluid and lung tissue was also markedly reduced in LPS-treated Cul-5-deficient mice. Interestingly, intratracheal adoptive transfer of Cul-5+/- but not Cul-5+/+ macrophages attenuated neutrophil recruitment, alveolar inflammation, and loss of barrier function in LPS-challenged wild-type mice. Finally, we demonstrated that Cul-5 neddylation following LPS exposure induced Cul-5 and TRAF6 interaction and, thereby, TFAR6 polyubiquitination, leading to NF-κB activation and generation of proinflammatory cytokines. Our data show that neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) modification of Cul-5 is required for its interaction with TRAF6 and activation of the TLR4-TRAF6 signaling pathway in LPS-induced ALI, a feature that may be explored for therapeutic intervention.

Keywords

Cullin-5; Nedd8; acute lung injury; macrophage.

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