1 Dept. of Microbiology, Faculty of Life Sci., Kumamoto Univ.2 Dept. of Occupational Therapy, Sch. of Rehabilitation, Tokyo Professional Univ. of Health Sci.3 Lab. for Evolutionary Cell Biology of the Skin, Sch. of Bioscience and Biotechnol., Tokyo Univ. of Technol.4 Dept. of Nursing, Kibi International Univ.5 Collaboration Unit for Infection, Joint Res. Center for Human Retrovirus Infection, Kumamoto Univ.Activation of human endogenous retroviruses by Sox proteins induces cell apoptosis via the caspase-3 pathway ○Md Jakir Hossain1 Nami Monde1 Hiroyuki Sasaki2 Perpetual Nyame1Wright Andrews Ofotsu Amesimeku1 Hiromi Terasawa1 Sojiro Matsumura1Takeshi Matsui3 Hiroyasu Tsutsuki1 Yosuke Maeda1,4 Tomohiro Sawa1 Kazuaki Monde1,5PurposeHuman endogenous retroviruses (HERVs) were domesticated millions of years ago as ancestral relics through germline infections and have become part of the human genome (8.3%). Over time, HERVs lost their innate ability to become virulent. We have previously reported that the transcription factor Sox2 is critical for human endogenous retrovirus-K (HERV-K) LTR5H activation and transposition in induced pluripotent stem cells. Therefore, the aspect of other Sox proteins in the activation of HERVs as well as the role of activated HERVs in Sox expressing cells are unknown. MethodsDifferent HERVs LTR were isolated from NCCIT cells and constructed the plasmid using Luciferase reporter gene. HeLa cells were co-transfected with pMXs Sox and pHERV-LTR Luciferase with internal control pRL TK Renilla. Venus and Luciferase expression were determined by flowcytometry and duel luciferase assay. The Sox protein dependent HERV-K Gag protein was detected by RT-qPCR, western blot, and confocal microscopy. The Sox dependent VLPs were detected by transmission and scanning electron microscopy. Using anti-HERV-K Gag and anti-Caspase-3 antibodies the HERV-K associated apoptotic cells were confirmed by confocal microscopy and flowcytometry. ResultsIn this study, we have found HERV-K LTR5H and LTR5B activation by Sox proteins. In addition, HERV-K Gag localized in the plasma membrane and virus-like particles were released from Sox-expressing cells. Notably, a deformed nucleus was induced by cleaved caspase-3 in the HERV-K Gag-expressing cells. The caspase-3 inhibitors increased the number of HERV-K Gag-expressing cells by inhibiting the apoptotic pathway. Furthermore, retrotransposition of HERV-K was significantly enhanced in Sox2-expressing cells treated with caspase-3 inhibitors.ConclusionsTaken together, these results indicate that several Sox proteins increase HERV-K expression with cleaved caspase-3, suggesting that induction of the cell apoptotic pathway prevents genome impairment by HERV-K expression and retrotransposition. 56P 026
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