The role of N-Glycan modification of TNFR1 in inflammatory microglia activation
- 452 Downloads
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.
KeywordsTNFα TNFR1 N-glycosylation Microglia activation NF-κB
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).
- 7.Zhang, J., Hawari, F.I., Shamburek, R.D., Adamik, B., Kaler, M., Islam, A., Liao, D.W., Rouhani, F.N., Ingham, M., Levine, S.J.: Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem. Biophys. Res. Commun. 366, 579–584 (2008)PubMedCentralCrossRefPubMedGoogle Scholar
- 8.Kohne, C., Johnson, A., Tom, S., Peers, D.H., Gehant, R.L., Hotaling, T.A., Brousseau, D., Ryll, T., Fox, J.A., Chamow, S.M., Berman, P.W.: Secretion of glycosylation site mutants can be rescued by the signal/pro sequence of tissue plasminogen activator. J. Cell. Biochem. 75, 446–461 (1999)CrossRefPubMedGoogle Scholar
- 12.Zhang, L., Connelly, J.J., Peppel, K., Brian, L., Shah, S.H., Nelson, S., Crosslin, D.R., Wang, T., Allen, A., Kraus, W.E., Gregory, S.G., Hauser, E.R., Freedman, N.J.: Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Hum. Mol. Genet. 19, 2754–2766 (2010)PubMedCentralCrossRefPubMedGoogle Scholar
- 14.Badiola, N., Malagelada, C., Llecha, N., Hidalgo, J., Comella, J.X., Sabria, J., Rodriguez-Alvarez, J.: Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol. Dis. 35, 438–447 (2009)CrossRefPubMedGoogle Scholar
- 16.Dellarole, A., Morton, P., Brambilla, R., Walters, W., Summers, S., Bernardes, D., Grilli, M., Bethea, J.R.: Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling. Brain Behav. Immun. 41, 65–81 (2014)CrossRefPubMedGoogle Scholar