A Human Endogenous Bornavirus-Like Nucleoprotein Encodes a Mitochondrial Protein Associated with Cell Viability
A Human Endogenous Bornavirus-Like Nucleoprotein Encodes a Mitochondrial Protein Associated with Cell Viability
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DOI：
10.1128/jvi.02030-20
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发表时间：
2021-07-01
影响因子：
5.4
通讯作者：
Tomonaga, Keizo
中科院分区：
文献类型：
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作者：
Fujino, Kan;Horie, Masayuki;Tomonaga, Keizo
内源性逆转录病毒（ERV）是动物基因组中源自古代逆转录病毒感染的序列;它们在进化过程中被选为功能基因或元件，为宿主提供遗传新奇。最近，我们证明，内源性元件不仅从逆转录病毒，但也非逆转录病毒RNA病毒是一个可能的来源，功能基因在宿主动物。古老的博尔纳病毒感染的残余物称为内源性博尔纳病毒样元件（EBL），存在于多种脊椎动物的基因组中，其中一些在宿主细胞中表达功能性产物。以前的研究预测，来源于博尔纳病毒核蛋白的人EBL基因座，称为hsEBLN-2，表达编码蛋白的mRNA，表明hsEBLN-2在进化过程中获得了细胞功能。然而，hsEBLN-2衍生产物的详细功能仍有待阐明。在这项研究中，我们表明，hsEBLN-2衍生的蛋白E2作为一种线粒体蛋白，与线粒体宿主因子与细胞凋亡，如HAX-1相互作用。我们还证明，敲低hsEBLN-2衍生的RNA增加了PARP和cas-pase-3切割的水平，并显着降低细胞活力。相反，在应激条件下，E2的过表达增强了细胞活力以及HAX-1的细胞内稳定性。我们的研究结果表明，hsEBLN-2已增选作为一个宿主基因，其产品是参与细胞活力与线粒体蛋白相互作用。重要信息我们的基因组中含有古老病毒的分子化石，称为内生病毒元件（EVES）。越来越多的证据表明，来自非逆转录病毒RNA病毒的EVE在进化过程中在宿主细胞中获得了功能。先前的研究表明，编码博尔纳病毒衍生的EVE（hsEBLN-2）的基因座可能与某些肿瘤的发生有关，该基因座约在4300万年前在人类祖先中产生。然而，hsEBLN-2的功能尚未确定。在这项研究中，我们发现，E2蛋白，hsEBLN-2的表达产物，相互作用与糖尿病相关的宿主蛋白作为线粒体蛋白，并影响细胞活力。这项研究表明，非逆转录病毒RNA病毒EVES已经被宿主吸收，其功能比以前认为的更多样化，显示了RNA病毒感染在进化中的关键作用。
Endogenous retroviruses (ERVs) are sequences in animal genomes that origi-nated from ancient retrovirus infections; they provide genetic novelty in hosts by being coopted as functional genes or elements during evolution. Recently, we demonstrated that endogenous elements from not only from retroviruses but also nonretroviral 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 prod-ucts in host cells. Previous studies have predicted that the human EBL locus derived from bornavirus nucleoprotein, termed hsEBLN-2, expresses mRNA encoding a protein, suggest -ing that hsEBLN-2 has acquired a cellular function during 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 acts as a mitochondrial protein that interacts with mitochondrial host factors associated with apoptosis, such as HAX-1. We also demon-strate that knockdown of hsEBLN-2-derived RNA increased the levels of PARP and cas-pase-3 cleavage and markedly decreased cell viability. In contrast, overexpression of E2 enhanced cell viability, as well as the intracellular stability of HAX-1, under stress condi-tions. Our results suggest that hsEBLN-2 has been coopted 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 endog-enous virus elements (EVEs). Mounting evidence suggests that EVEs derived from nonretroviral 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 nonretrovi-ral RNA viral EVEs have been coopted by hosts with more diverse functions than previously thought, showing a pivotal role for RNA virus infection in evolution.