SARS-CoV-2 ORF8 Exploits Host miRNA Networks to Rewire Post-Transcriptional Regulation
5 affiliations
- 1Immunogenomics and Molecular Pathogenesis Group, UIC Zoonoses and Emergent Diseases ENZOEM, Department of Genetics, University of Córdoba, 14071 Córdoba, Spain
- 2Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
- 3Viral Immunology Lab, BIC Unit, Molecular Biomedicine Department, Margarita Salas Center for Biological Research (CIB-CSIC), 28040 Madrid, Spain
- 4Biological Defense Area, CBRN Defense Department, General Subdirectorate for Terrestrial Systems—Campus “La Marañosa”, National Institute for Aerospace Technology (INTA), 28330 Madrid, Spain
- 5Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC, Calle Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several accessory proteins that modulate host cellular pathways and contribute to immune evasion and disease severity. Among them, ORF8 has emerged as a key immunomodulatory factor; however, its impact on host post-transcriptional regulatory networks remains poorly defined. In this study, we investigated how ORF8 expression reshapes the microRNA (miRNA) landscape of lung epithelial cells and how these changes translate into functional proteomic alterations. Using A549 cells transduced with ORF8 and control cells, we performed small RNA sequencing to identify differentially expressed miRNAs, followed by integrative analysis with quantitative proteomic data. ORF8 expression induces extensive remodeling of the miRNA profile, with coordinated upregulation and downregulation of miRNAs involved in inflammatory signaling, interferon regulation, apoptosis, autophagy and epithelial homeostasis. Integration of miRNA and proteomic datasets revealed inverse regulatory relationships linking ORF8-associated miRNAs to proteins involved in immune defense, stress responses and epithelial integrity. Selected miRNA alterations were validated by RT–qPCR, and the junctional protein plakoglobin (JUP) was experimentally confirmed as a representative downregulated target. Collectively, our findings identify ORF8 as a factor associated with coordinated miRNA-mediated post-transcriptional reprogramming in lung epithelial cells. This network-based regulatory framework provides new insight into how SARS-CoV-2 accessory proteins may influence host responses and highlights miRNA networks as potential contributors to viral pathogenesis and host immune dysregulation.
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BibTeX
@article{fernandezrodriguez2026sarscov2,
title = {{SARS-CoV-2 ORF8 Exploits Host miRNA Networks to Rewire Post-Transcriptional Regulation}},
author = {Raúl Fernández-Rodríguez and José M. Suárez-Cárdenas and Antonio Romero-Guillén and Blanca D. López-Ayllón and Fátima Milhano Santos and Ana de Lucas-Rius and Unai Merino-Herrán and Fernando Corrales and María Montoya and Juan J. Garrido and Tránsito García-García},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188363},
url = {https://www.mdpi.com/1422-0067/27/18/8363},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SARS-CoV-2 ORF8 Exploits Host miRNA Networks to Rewire Post-Transcriptional Regulation
AU - Raúl Fernández-Rodríguez
AU - José M. Suárez-Cárdenas
AU - Antonio Romero-Guillén
AU - Blanca D. López-Ayllón
AU - Fátima Milhano Santos
AU - Ana de Lucas-Rius
AU - Unai Merino-Herrán
AU - Fernando Corrales
AU - María Montoya
AU - Juan J. Garrido
AU - Tránsito García-García
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188363
UR - https://www.mdpi.com/1422-0067/27/18/8363
AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several accessory proteins that modulate host cellular pathways and contribute to immune evasion and disease severity. Among them, ORF8 has emerged as a key immunomodulatory factor; however, its impact on host post-transcriptional regulatory networks remains poorly defined. In this study, we investigated how ORF8 expression reshapes the microRNA (miRNA) landscape of lung epithelial cells and how these changes translate into functional proteomic alterations. Using A549 cells transduced with ORF8 and control cells, we performed small RNA sequencing to identify differentially expressed miRNAs, followed by integrative analysis with quantitative proteomic data. ORF8 expression induces extensive remodeling of the miRNA profile, with coordinated upregulation and downregulation of miRNAs involved in inflammatory signaling, interferon regulation, apoptosis, autophagy and epithelial homeostasis. Integration of miRNA and proteomic datasets revealed inverse regulatory relationships linking ORF8-associated miRNAs to proteins involved in immune defense, stress responses and epithelial integrity. Selected miRNA alterations were validated by RT–qPCR, and the junctional protein plakoglobin (JUP) was experimentally confirmed as a representative downregulated target. Collectively, our findings identify ORF8 as a factor associated with coordinated miRNA-mediated post-transcriptional reprogramming in lung epithelial cells. This network-based regulatory framework provides new insight into how SARS-CoV-2 accessory proteins may influence host responses and highlights miRNA networks as potential contributors to viral pathogenesis and host immune dysregulation.
SN - 1422-0067
ER -