Expression of Human Endogenous Retrovirus Group K (HERV-K) HML-2 Correlates with Immune Activation of Macrophages and Type I Interferon Response.

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    • Publication Information:
      Ahead of Print
    • Source:
      Publisher: ASM Press Country of Publication: United States NLM ID: 101634614 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2165-0497 (Electronic) Linking ISSN: 21650497 NLM ISO Abbreviation: Microbiol Spectr Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : ASM Press, 2013-
    • Abstract:
      Human endogenous retroviruses (HERVs) comprise about 8.3% of the human genome and are capable of producing RNA molecules that can be sensed by pattern recognition receptors, leading to the activation of innate immune response pathways. The HERV-K (HML-2) subgroup is the youngest HERV clade with the highest degree of coding competence. Its expression is associated with inflammation-related diseases. However, the precise HML-2 loci, stimuli, and signaling pathways involved in these associations are not well understood or defined. To elucidate HML-2 expression on a locus-specific level, we used the retroelement sequencing tools TEcount and Telescope to analyze publicly available transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data sets of macrophages treated with a wide range of agonists. We found that macrophage polarization significantly correlates with modulation of the expression of specific HML-2 proviral loci. Further analysis demonstrated that the provirus HERV-K102, located in an intergenic region of locus 1q22, constituted the majority of the HML-2 derived transcripts following pro-inflammatory (M1) polarization and was upregulated explicitly in response to interferon gamma (IFN-γ) signaling. We found that signal transducer and activator of transcription 1 and interferon regulatory factor 1 interact with a solo long terminal repeat (LTR) located upstream of HERV-K102, termed LTR12F, following IFN-γ signaling. Using reporter constructs, we demonstrated that LTR12F is critical for HERV-K102 upregulation by IFN-γ. In THP1-derived macrophages, knockdown of HML-2 or knockout of MAVS, an adaptor of RNA-sensing pathways, significantly downregulated genes containing interferon-stimulated response elements (ISREs) in their promoters, suggesting an intermediate role of HERV-K102 in the switch from IFN-γ signaling to the activation of type I interferon expression and, therefore, in a positive feedback loop to enhance pro-inflammatory signaling. IMPORTANCE The human endogenous retrovirus group K subgroup, HML-2, is known to be elevated in a long list of inflammation-associated diseases. However, a clear mechanism for HML-2 upregulation in response to inflammation has not been defined. In this study, we identify a provirus of the HML-2 subgroup, HERV-K102, which is significantly upregulated and constitutes the majority of the HML-2 derived transcripts in response to pro-inflammatory activation of macrophages. Moreover, we identify the mechanism of HERV-K102 upregulation and demonstrate that HML-2 expression enhances interferon-stimulated response element activation. We also demonstrate that this provirus is elevated in vivo and correlates with interferon gamma signaling activity in cutaneous leishmaniasis patients. This study provides key insights into the HML-2 subgroup and suggests that it may participate in enhancing pro-inflammatory signaling in macrophages and probably other immune cells.
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    • Contributed Indexing:
      Keywords: HERV-K; HERVs; HML-2; STAT signaling; Toll-like receptors; human endogenous retroviruses; inflammation; interferon gamma; interferon signaling; macrophage activation; type I interferons
    • Publication Date:
      Date Created: 20230302 Latest Revision: 20240216
    • Publication Date:
      20240216
    • Accession Number:
      PMC10100713
    • Accession Number:
      10.1128/spectrum.04438-22
    • Accession Number:
      36861980