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Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension

ABSTRACT: Human endogenous retroviral (HERV) proteins are induced by exogenous viruses or other factors that derepress HERV transcription and translation. Previously we showed that HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins are increased in monocytes and macrophages from patients with pulmonary arterial hypertension (PAH). Recombinant HERV-K dUTPase upregulates IL6 in pulmonary arterial endothelial cells (PAECs) and induces pulmonary hypertension in rats. However, it was not known how HERV-K dUTPase released from monocytes engages PAECs to upregulate IL6 or induces other PAH features of PAEC dysfunction. Here we report that HERV-K dUTPase recruits TLR4-myeloid differentiation primary response-88 to increase IL6 and SNAIL, the endothelial-mesenchymal transition (EndMT) transcription factor; HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) upregulates VCAM1. p38 and NF-kB are required to increase expression of all three genes, but in addition, pJNK-pSMAD3 is necessary for SNAIL upregulation, STAT1 for IL6, and pERK1/2-activating transcription factor-2 for VCAM1. Packaging of HERV-K dUTPase in monocyte-derived extracellular vesicles (EVs) induces SNAIL and subsequent EndMT in PAECs, IL6 and VCAM1. Mice infused with EVs from monocytes transfected with HERV-K dUTPase develop pulmonary hypertension. Thus, retroviral proteins delivered in EVs can overtake PAEC signaling and transcriptional machinery to induce dysfunction associated with PAH.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Marlene Rabinovitch

PROVIDER: MSV000086005 | MassIVE | Mon Aug 24 10:40:00 BST 2020

REPOSITORIES: MassIVE

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Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension

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