A human endogenous bornavirus-like nucleoprotein encodes a mitochondrial protein associated with cell viability.

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.ImportanceOur 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.