In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways
Introduction“In evolution’s unending race, survival demands continuous adaptation— to stop is to fall behind.” The Stimulator of Interferon Genes (STING) pathway embodies this principle, acting as a conserved master regulator of cytosolic DNA sensing from Drosophila to salmon and humans. Although ex...
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Frontiers Media S.A.
2025-06-01
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| author | Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Jorge F. Beltrán Claudia A. Barrientos Genaro Soto-Rauch Marcelo Aguilar Marcelo Aguilar Adolfo Isla Adolfo Isla Adolfo Isla Sandra N. Flores-Martin Francisco T. Yañez Yassef Yuivar Adriana Ojeda Felipe Almendras Patricio Bustos Marcos Mancilla |
| author_facet | Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Jorge F. Beltrán Claudia A. Barrientos Genaro Soto-Rauch Marcelo Aguilar Marcelo Aguilar Adolfo Isla Adolfo Isla Adolfo Isla Sandra N. Flores-Martin Francisco T. Yañez Yassef Yuivar Adriana Ojeda Felipe Almendras Patricio Bustos Marcos Mancilla |
| author_sort | Alejandro J. Yañez |
| collection | DOAJ |
| description | Introduction“In evolution’s unending race, survival demands continuous adaptation— to stop is to fall behind.” The Stimulator of Interferon Genes (STING) pathway embodies this principle, acting as a conserved master regulator of cytosolic DNA sensing from Drosophila to salmon and humans. Although extensively characterized in mammals, its structural features and regulatory roles during intracellular bacterial infection in teleosts remain poorly defined.MethodsWe structurally characterized the ancestral STING ortholog from Atlantic salmon (Salmo salar) using AlphaFold-guided modeling to identify conserved motifs, including the cyclic dinucleotide (CDN)-binding cleft and phosphorylation regulatory sites. Molecular docking simulations were performed to evaluate the interaction of a validated human STING agonist with salmonid STING. Transcriptomic analyses were conducted in immune tissues and SHK-1 macrophage-like cells infected with Piscirickettsia salmonis to assess gene expression dynamics.ResultsOur models confirmed evolutionary conservation of key STING structural domains. Docking revealed a strong binding affinity between the human agonist and salmonid STING, supporting translational potential. Transcriptomics showed high sting1 expression in immune tissues, rapidly upregulated after infection. In SHK-1 cells, STING1, IFN-α, TNF-α, and IL-1β peaked at 4 hours post-infection (hpi), but this inflammatory burst collapsed by 5 days post-infection (dpi), despite persistent sting1 transcription, indicating functional uncoupling due to immune evasion. In vivo, prolonged DDX41–STING activation was associated with reduced pyroptosis, necroptosis, and inflammatory signaling, reflecting bacterial suppression mechanisms.DiscussionThis study positions S. salar as a high-resolution model for STING biology and introduces the Evolutionary Molecular Immunity Race (EMIR) framework, where STING orchestrates immune fate across hundreds of millions of years of vertebrate evolution, and over the last ~80 million years within the salmonid lineage. |
| format | Article |
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| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-1e9d9cccf98d473eb07fc27ac77af4852025-08-20T03:31:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15708711570871In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathwaysAlejandro J. Yañez0Alejandro J. Yañez1Alejandro J. Yañez2Alejandro J. Yañez3Jorge F. Beltrán4Claudia A. Barrientos5Genaro Soto-Rauch6Marcelo Aguilar7Marcelo Aguilar8Adolfo Isla9Adolfo Isla10Adolfo Isla11Sandra N. Flores-Martin12Francisco T. Yañez13Yassef Yuivar14Adriana Ojeda15Felipe Almendras16Patricio Bustos17Marcos Mancilla18Departamento de Investigación y Desarrollo, Greenvolution SpA, Puerto Varas, Región de Los Lagos, ChileInterdisciplinary Center for Aquaculture Research (INCAR), Concepción, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileKeyBio Solution, Valdivia, Región de los Rios, ChileDepartment of Chemical Engineering, Universidad de la Frontera, Temuco, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileInterdisciplinary Center for Aquaculture Research (INCAR), Concepción, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileInterdisciplinary Center for Aquaculture Research (INCAR), Concepción, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileDepartamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomas, Valdivia, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileLaboratorio de Diagnóstico y Terapia, Vicerrectoría de Investigación, Desarrollo y Creación Artística (VIDCA), Universidad Austral de Chile, Valdivia, ChileLaboratorio de Diagnóstico y Biotecnología, ADL Diagnostic Chile, Puerto Montt, ChileLaboratorio de Diagnóstico y Biotecnología, ADL Diagnostic Chile, Puerto Montt, ChileDepartamento de Investigación y Desarrollo, Greenvolution SpA, Puerto Varas, Región de Los Lagos, ChileLaboratorio de Diagnóstico y Biotecnología, ADL Diagnostic Chile, Puerto Montt, ChileLaboratorio de Diagnóstico y Biotecnología, ADL Diagnostic Chile, Puerto Montt, ChileIntroduction“In evolution’s unending race, survival demands continuous adaptation— to stop is to fall behind.” The Stimulator of Interferon Genes (STING) pathway embodies this principle, acting as a conserved master regulator of cytosolic DNA sensing from Drosophila to salmon and humans. Although extensively characterized in mammals, its structural features and regulatory roles during intracellular bacterial infection in teleosts remain poorly defined.MethodsWe structurally characterized the ancestral STING ortholog from Atlantic salmon (Salmo salar) using AlphaFold-guided modeling to identify conserved motifs, including the cyclic dinucleotide (CDN)-binding cleft and phosphorylation regulatory sites. Molecular docking simulations were performed to evaluate the interaction of a validated human STING agonist with salmonid STING. Transcriptomic analyses were conducted in immune tissues and SHK-1 macrophage-like cells infected with Piscirickettsia salmonis to assess gene expression dynamics.ResultsOur models confirmed evolutionary conservation of key STING structural domains. Docking revealed a strong binding affinity between the human agonist and salmonid STING, supporting translational potential. Transcriptomics showed high sting1 expression in immune tissues, rapidly upregulated after infection. In SHK-1 cells, STING1, IFN-α, TNF-α, and IL-1β peaked at 4 hours post-infection (hpi), but this inflammatory burst collapsed by 5 days post-infection (dpi), despite persistent sting1 transcription, indicating functional uncoupling due to immune evasion. In vivo, prolonged DDX41–STING activation was associated with reduced pyroptosis, necroptosis, and inflammatory signaling, reflecting bacterial suppression mechanisms.DiscussionThis study positions S. salar as a high-resolution model for STING biology and introduces the Evolutionary Molecular Immunity Race (EMIR) framework, where STING orchestrates immune fate across hundreds of millions of years of vertebrate evolution, and over the last ~80 million years within the salmonid lineage.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1570871/fullSTING genedynamics activation gene expressionstructural functionsinnate immune responseAtlantic salmon-pathogen interactionevolutionary perspectives |
| spellingShingle | Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Alejandro J. Yañez Jorge F. Beltrán Claudia A. Barrientos Genaro Soto-Rauch Marcelo Aguilar Marcelo Aguilar Adolfo Isla Adolfo Isla Adolfo Isla Sandra N. Flores-Martin Francisco T. Yañez Yassef Yuivar Adriana Ojeda Felipe Almendras Patricio Bustos Marcos Mancilla In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways Frontiers in Immunology STING gene dynamics activation gene expression structural functions innate immune response Atlantic salmon-pathogen interaction evolutionary perspectives |
| title | In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| title_full | In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| title_fullStr | In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| title_full_unstemmed | In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| title_short | In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| title_sort | in evolution s unending race ancestral sting sensors in salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways |
| topic | STING gene dynamics activation gene expression structural functions innate immune response Atlantic salmon-pathogen interaction evolutionary perspectives |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1570871/full |
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