Editorial: Endogenous Viral Elements—Links Between Autoimmunity and Cancer?

Staege, Martin S.; Emmer, Alexander

doi:10.3389/fmicb.2018.03171

Cited by 7 publications

(8 citation statements)

References 7 publications

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“…dsRNA cancer therapies: There is a relation between autoimmune diseases and cancer—for example, long-standing autoimmune diseases may results in cancer transformation. Interestingly, the upregulation of ERV transcription is a common feature between these two pathologies [ 146 , 147 ]. The majority of ERVs are transcriptionally inactive, though 7% of their sequences can be reactivated by exogenous viruses or hypoxia [ 148 ].…”

Section: Physiological and Pathophysiological Roles Of Dsrnamentioning

confidence: 99%

Endogenous Double-Stranded RNA

Sadeq

Al-Hashimi

Cusack

et al. 2021

ncRNA

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The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation of repetitive elements in the genome. The transcription of endogenous retroviruses as well as long and short interspersed elements is not only essential for evolving lncRNAs but is also a significant source of double-stranded RNA (dsRNA). From an lncRNA-centric point of view, the latter is a minor source of bother in the context of the entire cell; however, dsRNA is an essential threat. A viral infection is associated with cytoplasmic dsRNA, and endogenous RNA hybrids only differ from viral dsRNA by the 5′ cap structure. Hence, a multi-layered defense network is in place to protect cells from viral infections but tolerates endogenous dsRNA structures. A first line of defense is established with compartmentalization; whereas endogenous dsRNA is found predominantly confined to the nucleus and the mitochondria, exogenous dsRNA reaches the cytoplasm. Here, various sensor proteins recognize features of dsRNA including the 5′ phosphate group of viral RNAs or hybrids with a particular length but not specific nucleotide sequences. The sensors trigger cellular stress pathways and innate immunity via interferon signaling but also induce apoptosis via caspase activation. Because of its central role in viral recognition and immune activation, dsRNA sensing is implicated in autoimmune diseases and used to treat cancer.

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Section: Physiological and Pathophysiological Roles Of Dsrnamentioning

confidence: 99%

Endogenous Double-Stranded RNA

Sadeq

Al-Hashimi

Cusack

et al. 2021

ncRNA

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“…While HERVs are highly expressed in embryonic stem cells, transcription and translation are repressed in differentiated cells (9). However, under certain circumstances, these control mechanisms can be subverted and this leads to the production of double stranded (ds) HERV RNA and Otsuki et al, page 4 HERV proteins linked to the pathology of cancer, autoimmune disease (10)(11)(12)(13), and most recently, PAH (14). The production of dsRNA induces a chronic interferon response, and HERV proteins, such as the HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase), can trigger innate as well as adaptive immune responses (15,16).…”

Section: Introductionmentioning

confidence: 99%

Monocyte released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition

Otsuki¹,

Saito²,

Taylor³

et al. 2021

JCI Insight

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Previously we reported heightened expression of human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of PA hypertension (PAH) patients. Furthermore, recombinant HERV-K dUTPase increased IL6 in PA endothelial cells (PAECs) and caused pulmonary hypertension in rats. Here we show that monocytes overexpressing HERV-K dUTPase as opposed to GFP, can release HERV-K dUTPase in extracellular vesicles (EVs) that cause pulmonary hypertension in mice in association with endothelial mesenchymal transition (EndMT) related to induction of SNAIL/SLUG, and proinflammatory molecules IL6 as well as VCAM1. In PAECs, HERV-K dUTPase requires TLR4myeloid differentiation primary response (MYD)-88 to increase IL6 and SNAIL/SLUG, and HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) is necessary to upregulate VCAM1. TLR4 engagement induces p-p38 activation of NF-κB in addition to pJNK-pSMAD3 required for SNAIL, and pSTAT1 for IL6. HERV-K dUTPase interaction with MCAM also induces p-p38 activation of NF-κB in addition to pERK1/2-activating transcription factor (ATF)-2 to increase VCAM1. Thus in PAH, monocytes or macrophages can release HERV-K dUTPase in EVs, and HERV-K dUTPase can engage dual receptors and signaling pathways to subvert PAEC transcriptional machinery to induce EndMT and associated pro-inflammatory molecules.

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“…Besides a beneficial effect, some HERV ENV are thought to contribute to diseases including cancer and autoimmune disorders [ 8 , 9 , 10 , 11 , 12 ]. Transcriptional activation of retroviral elements in pathologic tissues of soft tissue sarcoma patients or elevated antibody titers against viral proteins in the sera of patients with autoimmune rheumatic diseases were observed [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Formation of HERV-K and HERV-Fc1 Envelope Family Members is Suppressed on Transcriptional and Translational Level

Gröger

Wieland

Naumann

et al. 2020

IJMS

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The human genome comprises 8% sequences of retroviral origin, so-called human endogenous retroviruses (HERVs). Most of these proviral sequences are defective, but some possess open reading frames. They can lead to the formation of viral transcripts, when activated by intrinsic and extrinsic factors. HERVs are thought to play a pathological role in inflammatory diseases and cancer. Since the consequences of activated proviral sequences in the human body are largely unexplored, selected envelope proteins of human endogenous retroviruses associated with inflammatory diseases, namely HERV-K18, HERV-K113, and HERV-Fc1, were investigated in the present study. A formation of glycosylated envelope proteins was demonstrated in different mammalian cell lines. Nevertheless, protein maturation seemed to be incomplete as no transport to the plasma membrane was observed. Instead, the proteins remained in the ER where they induced the expression of genes involved in unfolded protein response, such as HSPA5 and sXBP1. Furthermore, low expression levels of native envelope proteins were increased by codon optimization. Cell-free expression systems showed that both the transcriptional and translational level is affected. By generating different codon-optimized variants of HERV-K113 envelope, the influence of single rare t-RNA pools in certain cell lines was demonstrated. The mRNA secondary structure also appears to play an important role in the translation of the tested viral envelope proteins. In summary, the formation of certain HERV proteins is basically possible. However, their complete maturation and thus full biologic activity seems to depend on additional factors that might be disease-specific and await elucidation in the future.

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Editorial: Endogenous Viral Elements—Links Between Autoimmunity and Cancer?

Cited by 7 publications

References 7 publications

Endogenous Double-Stranded RNA

Endogenous Double-Stranded RNA

Monocyte released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition

Formation of HERV-K and HERV-Fc1 Envelope Family Members is Suppressed on Transcriptional and Translational Level

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