{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:09:35Z","timestamp":1782835775145,"version":"3.54.5"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31801030, 31571269"],"award-info":[{"award-number":["31801030, 31571269"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010203","name":"Agriculture Research System of China","doi-asserted-by":"publisher","award":["CARS-41"],"award-info":[{"award-number":["CARS-41"]}],"id":[{"id":"10.13039\/501100010203","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Host antiviral defense relies on key regulatory genes that coordinate immune signaling and cellular homeostasis, yet their roles in J subgroup avian leukosis virus (ALV-J) infection remain poorly defined. Here, we identify cellular repressor of E1A-stimulated genes 1 (\n                      <jats:italic>CREG1<\/jats:italic>\n                      ) as a key regulator of mitochondrial function and a critical immune-related gene involved in ALV-J infection. The objective of this study was to explore the effects and underlying mechanisms of\n                      <jats:italic>CREG1<\/jats:italic>\n                      in the context of ALV-J infection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, transcriptomic analysis and RT-qPCR revealed that the expression of\n                      <jats:italic>CREG1<\/jats:italic>\n                      is significantly upregulated in the spleen tissues of ALV-J infected chickens. By overexpressing and silencing\n                      <jats:italic>CREG1<\/jats:italic>\n                      in cultured cells, and using Western blotting, transmission electron microscopy, immunofluorescence, and flow cytometry, we comprehensively validated its effects on viral replication, mitochondrial function, and apoptosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Overexpression of\n                      <jats:italic>CREG1<\/jats:italic>\n                      upregulates the expression of I-IFN and certain interferon-stimulated genes (ISGs), thereby suppressing viral replication. Mechanistically, overexpression of\n                      <jats:italic>CREG1<\/jats:italic>\n                      induces mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential (\u0394\u03c8m), reduced adenosine triphosphate (ATP) production and respiratory chain activity, enhanced mitophagy, and increased release of mitochondrial DNA (mtDNA), which in turn triggers the activation of innate immune responses. Mitochondrial dysfunction further leads to the cytosolic release of cytochrome c and an increase in reactive oxygen species (ROS) levels, thereby triggering a robust apoptotic response. Moreover, the regulation of mitochondrial function by CREG1 depends on its interaction with the mitochondrial chaperone protein heat shock protein 1 (HSPD1), and their co-expression synergistically amplifies the antiviral response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Overall, we identify\n                      <jats:italic>CREG1<\/jats:italic>\n                      as a potent antiviral gene and underscore the pivotal roles of mitochondria-mediated innate immunity and apoptosis during ALV-J infection.\n                    <\/jats:p>\n                  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