A Human Endogenous Bornavirus-Like Nucleoprotein Encodes a Mitochondrial Protein Associated with Cell Viability

Abstract

Endogenous retroviruses (ERVs) are sequences in animal genomes that originated from ancient retrovirus infections; they provide genetic novelty in hosts by being co-opted as functional genes or elements during evolution. Recently, we demonstrated that endogenous elements from not only retroviruses but also from non-retroviral RNA viruses are a possible source of functional genes in host animals. The remnants of ancient bornavirus infections, called endogenous bornavirus-like elements (EBLs), are present in the genomes of a wide variety of vertebrate species, and some express functional products in host cells. Previous studies have predicted that the human EBL locus derived from bornavirus nucleoprotein, termed hsEBLN-2, expresses mRNA encoding a protein, suggesting that hsEBLN-2 have acquired a cellular function during the evolution. However, the detailed function of the hsEBLN-2-derived product remains to be elucidated. In this study, we show that the hsEBLN-2-derived protein, E2, encodes a mitochondrial protein that interacts with mitochondrial host factors associated with apoptosis, such as HAX-1. We also demonstrate that knockdown of hsEBLN-2-derived RNA increased the levels of PARP and caspase-3 cleavage and markedly decreased the cell viability. In contrast, overexpression of E2 enhanced the cell viability, as well as the intracellular stability of HAX-1, under stress conditions. Our results suggest that hsEBLN-2 has been co-opted as a host gene, the product of which is involved in cell viability by interacting with mitochondrial proteins. Importance Our genomes contain molecular fossils of ancient viruses, called endogenous virus elements (EVEs). Mounting evidence suggests that EVEs derived from non-retroviral RNA viruses have acquired functions in host cells during evolution. Previous studies have revealed that a locus encoding a bornavirus-derived EVE, hsEBLN-2, which was generated approximately 43 million years ago in a human ancestor, may be linked to the development of some tumors. However, the function of hsEBLN-2 has not been determined. In this study, we found that the E2 protein, an expression product of hsEBLN-2, interacts with apoptosis-related host proteins as a mitochondrial protein and affects cell viability. This study suggests that non-retroviral RNA viral EVEs have been co-opted by hosts with more diverse functions than previously thought, showing a pivotal role for RNA virus infection in evolution.

Human Infections with Borna Disease Virus 1 (BoDV-1) Primarily Lead to Severe Encephalitis: Further Evidence from the Seroepidemiological BoSOT Study in an Endemic Region in Southern Germany

“…Since then, several homologous sequences of BoDV-1 N protein in the human genome and in the genome of a wide array of species were found and were termed as endogenous Bornavirus-like elements (EBLN). The tissue-dependent transcription of some of these genes as well as the translation of at least the ORF-encoding human EBLN hsEBLN-2 into a functional mitochondrial protein with certain functions was demonstrated [ 27 , 28 , 29 ]. In addition, homologous sequences for BoDV-1 M, G, and L protein have been found in the genome (termed EBLM, EBLG and EBLL) [ 27 ].…”

Comparative analysis reveals the long-term coevolutionary history of parvoviruses and vertebrates

“…The extent to which vertebrate EPVs have reached fixation through positive selection as opposed to incidental factors such as founder effects, population bottlenecks, and genetic hitchhiking remains unclear. Potentially, EPVs might sometimes be co-opted or “exapted” as has been reported for EVEs derived from other virus groups [ 44 – 46 ]. Recent studies have identified EPVs in the germline of degus ( Octodon degus ) and elephants (family Elephantidae) that encode intact Rep ORFs and exhibit similar patterns of tissue-specific mRNA expression in the liver [ 37 , 38 ], suggesting that expression of Rep protein or mRNA may be physiologically relevant in mammals.…”

Effect of different expression patterns of HAX-1 on the proliferation and apoptosis of human astrocyte

“…25,35,36 The HAX-1 has been preferentially located in the mitochondria in the cell, and in a small part, on the endoplasmic reticulum and nuclear membrane, which was primarily inferred to be related to cell apoptosis. 37 However, some studies have demonstrated that the effect of HAX-1 on apoptosis was controversial. Human and rat HAX-1 genes have been severely spliced, resulting in at least 7 different variants, mainly due to the differences in the NH2 ends.…”

“…43 The important role of HAX-1 in cell protection might also be related to the inhibition of mitochondrial and endoplasmic reticulum apoptosis pathways. 37 The HAX-1 also had certain effects on the nervous system. Studies have shown that HAX-1 had a neuroprotective effect against ischemic neuronal injury, and apoptosis after cerebral ischemia was induced by the downregulation of HAX-1 by NOX2-produced reactive oxygen species (ROS).…”