Related Endogenous Retrovirus-K Elements Harbor Distinct Protease Active Site Motifs

Abstract

Background: Endogenous retrovirus-K is a group of related genomic elements descending from retroviral infections in human ancestors. HML2 is the clade of these viruses which contains the most intact provirus copies. These elements can be transcribed and translated in healthy and diseased tissues, and some of them produce active retroviral enzymes, such as protease. Retroviral gene products, including protease, contribute to illness in exogenous retroviral infections. There are ongoing efforts to test anti-retroviral regimens against endogenous retroviruses. Herein, we examine the potential activity and diversity of human endogenous retrovirus-K proteases, and their potential for impact on immunity and human disease.Results: Sequences similar to the endogenous retrovirus-K HML2 protease and reverse transcriptase were identified in the human genome, classified by phylogenetic inference and compared to Repbase reference sequences. The topologies of trees inferred from protease and reverse transcriptase sequences were similar and agreed with the classification using reference sequences. Surprisingly, only 62/480 protease sequences identified by BLAST were classified as HML2; the remainder were classified as other HML groups, with the majority (216) classified as HML3. Variation in functionally significant protease motifs was explored, and two major active site variants were identified – the DTGAD variant is common in all groups, but the DTGVD motif appears limited to HML3, HML5, and HML6. Furthermore, distinct RNA expression patterns of protease variants are seen in disease states, such as amyotrophic lateral sclerosis, breast cancer, and prostate cancer.Conclusion: Transcribed ERVK proteases exhibit a diversity which could impact immunity and inhibitor-based treatments, and these facets should be considered when designing therapeutic regimens.

Faecal virome of the Australian grey-headed flying fox from urban/suburban environments contains novel coronaviruses, retroviruses and sapoviruses

“…Four ORFs were observed over the 7,455 bp genome and assigned as the gag, pro, pol and env genes based on the presence of conserved domains. In the pro gene we were able to identify an active site motif DTGAD predominately observed in functional retroviruses, and a helix motif GRDVL (Turnbull and Douville, 2018). We were unable to identify complete long terminal repeat (LTR) regions in the 7,455 bp genome, although this may be due to incomplete assembly at the 5’ and/or 3’ end, rather than a true absence of LTRs.…”

Detection and Characterisation of an Endogenous Betaretrovirus in Australian Wild Deer

“…In general, pro-encoded proteins have two domains, a pseudoprotease (protease-like) domain that has deoxyuridine triphosphatase (dUTPase) activity and an active protease (PR) [28,29]. We found that the CERV β1 pro contains a dUTPase domain at its 5′ end (Figure 1), and the protease activity was confirmed since this sequence bears the core amino acid sequence of a retroviral aspartyl protease Leu-Asp-Thr-Gly (nt 2536-2547) [28,30]. Interestingly, such as other betaretroviruses [6], CERV β1 pro encodes a glycine-rich region called the G-patch domain [31].…”

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

“…Ethically-sourced human autopsy tissues were obtained from the NIH Neurobiobank and the Veterans Affairs Brain Bank. Cell culture, transfections, cytokine treatments, western blot, chromatin immunoprecipitation, quantitative PCR, immunohistochemistry/histological staining, RNAseq analysis, and computational biology were done as described previously [7,8,[47][48][49]. Detailed descriptions of the methodologies are provided in Supplementary Methods.…”