Abstract
About 8 % of the human genome consists of human endogenous retroviruses (HERVs), which are relicts of ancient exogenous retroviral infections incurred during evolution. Although the majority of HERVs have functional gene defects or epigenetic modifications, many of them are still able to produce retroviral proteins that have been proposed to be involved in cellular transformation and cancer development.We found that, in chemo-resistant U87RETO glioblastoma cells, cytotoxic stress induced by etoposide promotes accumulation and large-scale fission of mitochondria, associated with the detection of HERV-WE1 (syncytin-1) and HERV-FRD1 (syncytin-2) in these organelles. In addition, mitochondrial preparations also contained the corresponding receptors, i.e. ASCT2 and MFSD2. We clearly demonstrated that mitochondria associated with HERV-proteins were shuttled between adjacent cancer cells not only via tunneling tubes, but also by direct cellular uptake across the cell membrane. Furthermore, anti-syncytin-1 and anti-syncytin-2 antibodies were able to specifically block this direct cellular uptake of mitochondria even more than antibodies targeting the cognate receptors.Here, we suggest that the association of mitochondria with syncytin-1/syncytin-2 together with their respective receptors could represent a novel mechanism of cell-to-cell transfer. In chemotherapy-refractory cancer cells, this might open up attractive avenues to novel mitochondria-targeting therapies.
Highlights
The human genome contains several copies of human endogenous retroviruses or human endogenous retrovirus DMEM (HERV), constituting about 8 % of the genetic material [1,2,3,4,5,6,7,8]
About 8 % of the human genome consists of human endogenous retroviruses (HERVs), which are relicts of ancient exogenous retroviral infections incurred during evolution
We demonstrate that cytotoxic stress by etoposide induces accumulation of mitochondria in human U87 glioblastoma cells, which were associated with different HERV-envelope proteins including, significantly, HERV-WE1 and HERV-FRD1
Summary
The human genome contains several copies of human endogenous retroviruses or HERVs, constituting about 8 % of the genetic material [1,2,3,4,5,6,7,8]. The individual subclasses are defined by the predicted tRNA specificity of the binding site at which reverse transcription will be initiated [1,2,3,4,5] In contrast to their retroviral ancestors and murine or porcine counterparts, HERVs have not been reported to generate infectious viral particles in humans. Due to mutations and epigenetic modifications, they have lost the capacity of horizontal transmission and are merely inherited as a part of the genome. Most of their LTRs have retained functional promotors, and many HERVs do contain protein-encoding genes [6,7,8,9,10]. The envelope protein from multiple sclerosis (MS) associated retroviral element (MSARV), a member of the HERV-type W, induces impaired immunity and promotes inflammation [15]
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