Bovine Delta Papillomavirus E5 Oncoprotein Interacts With TRIM25 and Hampers Antiviral Innate Immune Response Mediated by RIG-I-Like Receptors

Abstract

Persistent infection and tumourigenesis by papillomaviruses (PVs) require viral manipulation of various of cellular processes, including those involved in innate immune responses. Herein, we showed that bovine PV (BPV) E5 oncoprotein interacts with a tripartite motif-containing 25 (TRIM25) but not with Riplet in spontaneous BPV infection of urothelial cells of cattle. Statistically significant reduced protein levels of TRIM25, retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) were detected by Western blot analysis. Real-time quantitative PCR revealed marked transcriptional downregulation of RIG-I and MDA5 in E5-expressing cells compared with healthy urothelial cells. Mitochondrial antiviral signalling (MAVS) protein expression did not vary significantly between diseased and healthy cells. Co-immunoprecipitation studies showed that MAVS interacted with a protein network composed of Sec13, which is a positive regulator of MAVS-mediated RLR antiviral signalling, phosphorylated TANK binding kinase 1 (TBK1), and phosphorylated interferon regulatory factor 3 (IRF3). Immunoblotting revealed significantly low expression levels of Sec13 in BPV-infected cells. Low levels of Sec13 resulted in a weaker host antiviral immune response, as it attenuates MAVS-mediated IRF3 activation. Furthermore, western blot analysis revealed significantly reduced expression levels of pTBK1, which plays an essential role in the activation and phosphorylation of IRF3, a prerequisite for the latter to enter the nucleus to activate type 1 IFN genes. Our results suggested that the innate immune signalling pathway mediated by RIG-I-like receptors (RLRs) was impaired in cells infected with BPVs. Therefore, an effective immune response is not elicited against these viruses, which facilitates persistent viral infection.

Bovine delta papillomavirus E5 oncoprotein negatively regulates the cGAS-STING signaling pathway in cattle in a spontaneous model of viral disease

“…Detailed virological findings involving these samples have been reported previously. Briefly, we detected E5 oncoprotein transcripts by RT-PCR, the sequencing of which showed 100% identity with BPV-2 and BPV-13 in 15 neoplastic bladders of cattle (Accession numbers M20219.1 and JQ798171.1, respectively) ( 25 ). One-Step RT-ddPCR analysis failed to detect any E5 mRNA from four bovine Delta papillomaviruses in both “non-infected” and healthy bladders ( Supplemental Figures 1A, B ), thus showing that these animals did not harbor any abortive papillomavirus infection.…”

“…The co-evolution of oncogenic BPVs with transforming urothelial cells suggests that BPVs can develop mechanisms that lead to the shutdown of the host immune system, which allows BPVs to escape immune responses. Recently, BPV E5 oncoprotein was shown to negatively regulate the host antiviral innate immune response via retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) in a spontaneous model of bovine papillomavirus disease in cattle ( 25 ).…”

Pteridium spp. and Bovine Papillomavirus: Partners in Cancer

“…Interestingly, the immunotoxic effects of ptaquiloside against NK cells in mice could be reversed with selenium administration ( 109 ), suggesting that prevention of bracken fern toxicities can be achievable through dietary modifications. Very recently, the E5 oncoprotein of Delta BPVs was shown to impair the production of type I interferon and the innate antiviral response via interactions with the tripartite motif-containing 25 (TRIM25) protein ( 110 ), further establishing the immune evasion mechanisms employed by BPV.…”

SEA and GATOR 10 Years Later

“…Recently, SESTRIN2, which interacts with GATOR2 during leucine starvation (see above), was also found to be localized to mitochondria and silencing of GATOR2 genes considerably reduced the mitochondrial pool of SESTRIN2 [144]. Finally, Sec13 was shown to be interacting with mitochondrial antiviral signal protein (MAVS, also known as VISA) [145,146]. MAVS is localized on the outer membrane of mitochondria, with a small proportion present at mitochondria-associated membranes (MAMs).…”