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The role of N-Glycan modification of TNFR1 in inflammatory microglia activation

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Abstract

Accumulating evidences demonstrated that microglia activation and the autocrine loop of tumor necrosis factor-α (TNFα) greatly contribute to the pathogenesis of several CNS diseases. TNFα exerts its biological effects by interacting with two different receptors: TNF receptor 1 (TNFR1) and TNFR2. The classic proinflammatory activity of TNFα is mainly mediated by TNFR1. In the present study, we found that TNFR1 was modificated by N-glycosylation on Asn151 and Asn202 in microglia. The N-glycosylation of TNFR1 could facilitate its capability of binding to TNFα and further promote the formation of TNFα autocrine loop in microglia stimulated by TNFα, resulting in excessive microglia activation and CNS inflammation. All these processes were related to TNFR1-mediated NF-κB pathways. Elimination of N-glycosylation did not affect the subcellular transportation and cell surface localization of TNFR1, but suppressed ligand-binding affinity. These findings indicated that the N-glycosylation of TNFR1 played an important role during microglia activation in CNS inflammation. By this study, we aimed to provide some valuable experimental evidence for a better understanding of the significance of protein glycosylation in microglia inflammatory activation and CNS disease.

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Acknowledgments

This work was supported by the National Basic Research Program of China (973 Program, No.2012CB822104); the National Natural Science Foundation of China (No.31500647, No.81371299, No.31440037, No.31270802); the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (15KJA310003); the Natural Science Foundation of Jiangsu Province (BK20150408); a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226000, Jiangsu, People’s Republic of China

      Lijian Han, Liang Zhu, Yu Zhang & Kaifu Ke

    2. The Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226000, Jiangsu, People’s Republic of China

      Lijian Han, Dongmei Zhang, Tao Tao, Xiaolei Sun, Xiaojuan Liu, Guizhou Zhu, Zhiwei Xu, Liang Zhu, Yu Zhang, Wangrui Liu & Aiguo Shen

    3. Department of Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, Jiangsu, People’s Republic of China

      Aiguo Shen

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    1. Lijian Han
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    Correspondence to Kaifu Ke or Aiguo Shen.

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    Lijian Han and Dongmei Zhang contributed equally to this work.

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    Han, L., Zhang, D., Tao, T. et al. The role of N-Glycan modification of TNFR1 in inflammatory microglia activation. Glycoconj J 32, 685–693 (2015). https://doi.org/10.1007/s10719-015-9619-1

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    • DOI: https://doi.org/10.1007/s10719-015-9619-1

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