{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:38:36Z","timestamp":1793129916612,"version":"4.5.0"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"The National Key Research and Development Program of China","award":["2025YFD1800400"],"award-info":[{"award-number":["2025YFD1800400"]}]},{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["3257190991"],"award-info":[{"award-number":["3257190991"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Natural Science Foundation of Jilin Province of China","award":["20250602022RC"],"award-info":[{"award-number":["20250602022RC"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Rabies virus (RABV), a lethal neurotropic pathogen, relies on interaction with the host to sustain neuronal infection; however, how it balances replication with neuronal survival remains unclear. Here, we revealed Snapin, a neuronal trafficking regulator, to be a critical host factor co-opted by RABV to enhance neuroinvasion. We found that RABV infection upregulated Snapin expression in N2a cells, and Snapin could promote the replication of RABV CVS11 and SRV9 strains in a dose-dependent manner. Mechanistic studies demonstrated that RABV P protein interacts with the 37\u201378 aa domain of Snapin via its C-terminal domain (172\u2013297 aa), recruits glycogen synthase kinase 3\u03b2 (GSK3\u03b2) in a Snapin-dependent manner, and forms a tripartite complex. Upon complex formation, the phosphorylation level at the Tyr216 site of GSK3\u03b2 is increased, leading to activation of the NF-\u03baB pathway. This activation enhances viral replication by upregulating neuronal stability genes (\n                      <jats:italic toggle=\"yes\">Septin2, B4gat1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Disc1<\/jats:italic>\n                      ) without inducing interferon responses.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      studies show that knockdown of Snapin in infected mice delays clinical symptom onset and improves host survival. This study uncovers a unique strategy wherein RABV exploits Snapin as a molecular scaffold linking P to GSK3\u03b2\/NF-\u03baB signaling, coupling viral replication to neuronal homeostasis. Our work identifies a host-dependent axis for therapeutic targeting in rabies and offers broader implications for understanding neurotropic pathogens utilizing analogous mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Rabies virus (RABV) depends on host factors to maintain neuronal infection while avoiding cell death, but the mechanisms balancing viral replication and neuronal survival are unclear. This study identifies Snapin as a critical host factor commandeered by RABV to enhance neuroinvasion. Upon RABV infection, Snapin is upregulated and subsequently hijacked by the C-terminal domain of the RABV P protein. This interaction recruits GSK3\u03b2 in a Snapin-dependent manner, forming a tripartite complex that increases phosphorylation of GSK3\u03b2 at Tyr216 and activates the NF-\u03baB pathway. Such activation upregulates neuronal stability genes (\n                      <jats:italic toggle=\"yes\">Septin2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">B4gat1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Disc1<\/jats:italic>\n                      ), thereby promoting viral replication without eliciting interferon responses.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      functional validation further confirms that Snapin deficiency attenuates RABV pathogenicity and prolongs host survival. Collectively, our study highlights a Snapin-dependent GSK3\u03b2\/NF-\u03baB axis as a potential therapeutic target for rabies treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01006-26","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:00:17Z","timestamp":1789477217000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["RABV P protein activates the GSK3\u03b2-NF-\u03baB signaling pathway to promote viral replication by interacting with the host protein Snapin"],"prefix":"10.1128","volume":"100","author":[{"given":"Yujie","family":"Bai","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00js3aw79","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 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