Multiomics Profiling of HERV Modulation and Immune Activation via RIG-I and IFNAR Pathways in Human Airway Epithelial Cells
Human Endogenous Retroviruses (HERVs) represent 8% of the human genome and originate from ancient retroviral infections of the primate germline. Despite the accumulation of mutations, many HERVs retained transcriptional activity and, occasionally, coding potential. Among their physiological roles, HERV involvement in the evolution of antiviral defences is well established, regulating the transcription of nearby genes and modulating innate immunity.  In this study, transcriptome and proteome profiling of human non-tumoral airway epithelial cells (BEAS-2B) were integrated to capture global gene and protein expression changes, together with the modulation of HERV loci. The study focused on two distinct immune activation checkpoints: RIG-I, a key player in RNA virus detection, and downstream IFNAR interferon receptors.  Results showed that these two immune stimulations orchestrate gene and protein expression in distinct, yet partially overlapping ways. While some cellular pathways were commonly activated, others were uniquely regulated, highlighting treatment-specific signatures. HERV expression was significantly influenced by immune activation, with 74 modulated loci following RIG-I activation compared to only 3 under IFN-alpha2A treatment, demonstrating RIG-I's broader impact on HERV expression consistent with its role in antiviral signalling. De novo transcriptome reconstruction further allowed exploration of the integration context of individual HERV loci and hypothesis of their functional roles.  This work provides the first detailed characterization of the interplay between HERV expression and two main antiviral immune activation pathways.
Human Endogenous Retroviruses (HERVs) represent 8% of the human genome and originate from ancient retroviral infections of the primate germline. Despite the accumulation of mutations, many HERVs retained transcriptional activity and, occasionally, coding potential. Among their physiological roles, HERV involvement in the evolution of antiviral defences is well established, regulating the transcription of nearby genes and modulating innate immunity.  In this study, transcriptome and proteome profiling of human non-tumoral airway epithelial cells (BEAS-2B) were integrated to capture global gene and protein expression changes, together with the modulation of HERV loci. The study focused on two distinct immune activation checkpoints: RIG-I, a key player in RNA virus detection, and downstream IFNAR interferon receptors.  Results showed that these two immune stimulations orchestrate gene and protein expression in distinct, yet partially overlapping ways. While some cellular pathways were commonly activated, others were uniquely regulated, highlighting treatment-specific signatures. HERV expression was significantly influenced by immune activation, with 74 modulated loci following RIG-I activation compared to only 3 under IFN-alpha2A treatment, demonstrating RIG-I's broader impact on HERV expression consistent with its role in antiviral signalling. De novo transcriptome reconstruction further allowed exploration of the integration context of individual HERV loci and hypothesis of their functional roles.  This work provides the first detailed characterization of the interplay between HERV expression and two main antiviral immune activation pathways.
Universita degli Studi di Cagliari