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The role of N-glycan modification of TNFR1 in inflammatory microglia activation
Lijian Han1,2, Dongmei Zhang2, Tao Tao2
1Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226000, Jiangsu, People's Republic of China.
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.
Insights
N-glycosylation of tumor necrosis factor-α receptor 1 (TNFR1) in microglia enhances its binding to TNFα, promoting CNS inflammation. This discovery offers new insights into protein glycosylation
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia activation and tumor necrosis factor-α (TNFα) signaling are key in central nervous system (CNS) diseases.
- TNFα exerts effects via TNF receptor 1 (TNFR1) and TNFR2, with TNFR1 mediating classic pro-inflammatory activity.
Purpose of the Study:
- To investigate the role of N-glycosylation of TNFR1 in microglia activation and CNS inflammation.
- To elucidate the molecular mechanisms by which TNFR1 glycosylation influences TNFα binding and downstream signaling.
Main Methods:
- Identifying N-glycosylation sites on TNFR1 in microglia.
- Assessing the impact of N-glycosylation on TNFR1's binding affinity to TNFα.
- Analyzing TNFR1-mediated NF-κB pathway activation in response to TNFα stimulation.
Main Results:
- TNFR1 is N-glycosylated at Asn151 and Asn202 in microglia.
- N-glycosylation enhances TNFR1 binding to TNFα, promoting the TNFα autocrine loop.
- This process leads to excessive microglia activation and CNS inflammation via TNFR1-mediated NF-κB pathways.
- Eliminating N-glycosylation reduced ligand-binding affinity without affecting receptor localization.
Conclusions:
- N-glycosylation of TNFR1 is a critical regulator of microglia activation in CNS inflammation.
- Targeting TNFR1 N-glycosylation may offer a novel therapeutic strategy for CNS inflammatory diseases.
- Protein glycosylation plays a significant role in neuroinflammation.
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