Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Dembny, Paul; Newman, Andrew G.; Singh, Manvendra; Hinz, Michael; Szczepek, Michal; Krüger, Christa; Adalbert, Róbert; Dzaye, Omar; Trimbuch, Thorsten; Wallach, Thomas; Kleinau, Gunnar; Derkow, Katja; Richard, Bernhard Clemens; Schipke, Carola G.; Scheidereit, Claus; Stachelscheid, Harald; Golenbock, Douglas T.; Peters, Oliver; Coleman, Michael P.; Heppner, Frank L.; Scheerer, Patrick; Tarabykin, Victor; Ruprecht, Klemens; Izsvák, Zsuzsanna; Mayer, Jens; Lehnardt, Seija

doi:10.1172/jci.insight.131093

Cited by 90 publications

(81 citation statements)

References 54 publications

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“…HERV-derived dsRNA has been reported to be sensed by Toll-like receptor 3 (TLR3) and mitochondrial antiviral signalling protein (MAVS) to stimulate a robust interferon response (102,103). HML-2 RNA was specifically shown to bind human Toll-like receptor 8 (TLR8) and murine Tlr7 leading to canonical NF-kB (p50/p65) pathway activation (104).…”

Section: Immune Modulation/evasionmentioning

confidence: 99%

Ancient Adversary – HERV-K (HML-2) in Cancer

et al. 2021

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Human endogenous retroviruses (HERV), ancient integrations of exogenous viruses, make up 8% of our genome. Long thought of as mere vestigial genetic elements, evidence is now accumulating to suggest a potential functional role in numerous pathologies including neurodegenerative diseases, autoimmune disorders, and multiple cancers. The youngest member of this group of transposable elements is HERV-K (HML-2). Like the majority of HERV sequences, significant post-insertional mutations have disarmed HERV-K (HML-2), preventing it from producing infectious viral particles. However, some insertions have retained limited coding capacity, and complete open reading frames for all its constituent proteins can be found throughout the genome. For this reason HERV-K (HML-2) has garnered more attention than its peers. The tight epigenetic control thought to suppress expression in healthy tissue is lost during carcinogenesis. Upregulation of HERV-K (HML-2) derived mRNA and protein has been reported in a variety of solid and liquid tumour types, and while causality has yet to be established, progressively more data are emerging to suggest this phenomenon may contribute to tumour growth and metastatic capacity. Herein we discuss its potential utility as a diagnostic tool and therapeutic target in light of the current in vitro, in vivo and clinical evidence linking HERV-K (HML-2) to tumour progression.

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Section: Immune Modulation/evasionmentioning

confidence: 99%

Ancient Adversary – HERV-K (HML-2) in Cancer

et al. 2021

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“…KEGG pathways for several ERVK-associated neurological conditions were identified, including ALS [9,12], Alzheimer's disease [89], and prion disease [90] (Figure 4). Specifically, long-term potentiation and synaptic neurotransmitter release (dopaminergic, glutamatergic, cholinergic, serotonergic, and GABAergic) were associated with the ERVK IN interactome.…”

Section: Neurological Diseasementioning

confidence: 99%

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

2021

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Integrase (IN) enzymes are found in all retroviruses and are crucial in the retroviral integration process. Many studies have revealed how exogenous IN enzymes, such as the human immunodeficiency virus (HIV) IN, contribute to altered cellular function. However, the same consideration has not been given to viral IN originating from symbionts within our own DNA. Endogenous retrovirus-K (ERVK) is pathologically associated with neurological and inflammatory diseases along with several cancers. The ERVK IN interactome is unknown, and the question of how conserved the ERVK IN protein–protein interaction motifs are as compared to other retroviral integrases is addressed in this paper. The ERVK IN protein sequence was analyzed using the Eukaryotic Linear Motif (ELM) database, and the results are compared to ELMs of other betaretroviral INs and similar eukaryotic INs. A list of putative ERVK IN cellular protein interactors was curated from the ELM list and submitted for STRING analysis to generate an ERVK IN interactome. KEGG analysis was used to identify key pathways potentially influenced by ERVK IN. It was determined that the ERVK IN potentially interacts with cellular proteins involved in the DNA damage response (DDR), cell cycle, immunity, inflammation, cell signaling, selective autophagy, and intracellular trafficking. The most prominent pathway identified was viral carcinogenesis, in addition to select cancers, neurological diseases, and diabetic complications. This potentiates the role of ERVK IN in these pathologies via protein–protein interactions facilitating alterations in key disease pathways.

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“…The overexpression of HERV RNAs (dsRNA) is sensed by intracellular pattern recognition receptors (PRRs) [28,29,35] and may induce a viral mimicry state, leading to an inflammatory environment able to recruit numerous immune cells to the tumor site. Indeed, the inherent DNA hypomethylation in some tumors may result in the activation and overexpression of HERVs.…”

Section: Viral Mimicry Statementioning

confidence: 99%

“…Two major classes of PRRs, including Toll-like receptors (TLRs) and retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) are known to be activated by endogenous retroviruses in humans and mice [28,29,35,38].…”

Section: Viral Mimicry Statementioning

confidence: 99%

Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

Petrizzo

Ragone

Cavalluzzo

et al. 2021

Cancers

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Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a “danger signal” by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy.

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Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Cited by 90 publications

References 54 publications

Ancient Adversary – HERV-K (HML-2) in Cancer

Ancient Adversary – HERV-K (HML-2) in Cancer

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

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