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However, the signal mechanism of N-protein in the lung inflammatory response remains poorly understood. The goal of this study was to determine whether RAGE (receptor for advanced glycation endproducts) participated in N-protein\u2013induced acute lung injury. The binding between N-protein and RAGE was examined via assays for protein\u2013protein interaction. To determine the signaling mechanism in vitro, cells were treated with recombinant N-protein and assayed for the activation of the RAGE\/MAPK (mitogen-activated protein kinase)\/NF-\u0138B pathway. RAGE deficiency mice and antagonist were used to study N-protein\u2013induced acute lung injury in vivo. Binding between N-protein and RAGE was confirmed via flow cytometry\u2013based binding assay, surface plasmon resonance, and ELISA. Pull-down and coimmunoprecipitation assays revealed that N-protein bound RAGE via both N-terminal and C-terminal domains. In vitro, N-protein activated the RAGE-ERK1\/2\u2013NF-\u0138B signaling pathway and induced a proinflammatory response. RAGE deficiency subdued N-protein\u2013induced proinflammatory signaling and response. In vivo, RAGE was upregulated in the BAL and lung tissue after recombinant N-protein insult. RAGE deficiency and small molecule antagonist partially protected mice from N-protein\u2013induced acute lung injury. Our study demonstrated that RAGE is a receptor for N-protein. RAGE is partially responsible for N-protein\u2013induced acute lung injury and has the potential to become a therapeutic target for treating coronavirus disease.<\/jats:p>","DOI":"10.1165\/rcmb.2022-0351oc","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T15:01:45Z","timestamp":1689951705000},"page":"508-520","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":18,"title":["RAGE Is a Receptor for SARS-CoV-2 N Protein and Mediates N Protein\u2013induced Acute Lung Injury"],"prefix":"10.1093","volume":"69","author":[{"given":"Jie","family":"Xia","sequence":"first","affiliation":[{"name":"The Children\u2019s Hospital of Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangmei","family":"Wang","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of 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