Activation of human endogenous retroviruses by Sox proteins induces cell apoptosis via the caspase-3 pathway

Md Jakir Hossain¹Nami Monde¹Hiroyuki Sasaki²Perpetual Nyame¹Wright Andrews Ofotsu Amesimeku¹Hiromi Terasawa¹Sojiro Matsumura¹Takeshi Matsui³Hiroyasu Tsutsuki¹Yosuke Maeda^1,4Tomohiro Sawa¹Kazuaki Monde^5,6*

• ¹Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
• ²Department of Occupational Therapy, School of Rehabilitation, Tokyo Professional University of Health Sciences, Tokyo, Japan
• ³Laboratory for Evolutionary Cell Biology of the Skin, School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan
• ⁴Department of Nursing, Kibi International University, Okayama, Japan
• ⁵Kumamoto University, Kumamoto, Japan
• ⁶Collaboration Unit for Infection, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Chiba, Japan

Human 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. In the present study, we identified HERV-K LTR5H and LTR5B activation following Sox overexpression. In addition, we found that HERV-K Gag localized in the plasma membrane and that 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. Taken 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.