Endonucleosis mediates internalization of cytoplasm into the nucleus

• Published in: Nature communications 2024-07, Vol.15 (1), p.5843-18, Article 5843
• Main Authors: Galanopoulou, Ourania, Tachmatzidi, Evangelia C., Deligianni, Elena, Botskaris, Dimitris, Nikolaou, Kostas C., Gargani, Sofia, Dalezios, Yannis, Chalepakis, Georges, Talianidis, Iannis
• Format: Article
• Language: English
• Subjects: 14; 14/28; 14/32; 14/63; 45; 45/15; 45/91; 631/337/1427; 631/80/386; 631/80/509; 64; 64/60; Animals; Autophagy; Autophagy - physiology; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Cell death; Cell Nucleus - metabolism; Cellular stress response; Condensates; Cytology; Cytoplasm; Cytoplasm - metabolism; Damage prevention; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; Glycogen; Glycogens; Hepatocytes; Hepatocytes - metabolism; Humanities and Social Sciences; Internalization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Necrosis; Nuclei; Nuclei (cytology); Organelles; Science; Science (multidisciplinary); Senescence; Survival; Transcription elongation; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50259-3

Setd8 regulates transcription elongation, mitotic DNA condensation, DNA damage response and replication licensing. Here we show that, in mitogen-stimulated liver-specific Setd8-KO mice, most of the hepatocytes are eliminated by necrosis but a significant number of them survive via entering a stage exhibiting several senescence-related features. Setd8-deficient hepatocytes had enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles surrounded by nuclear lamina. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process “endonucleosis”. Intranuclear vesicles are absent in hepatocytes of Setd8/Atg5 knockout mice, suggesting that the process requires the function of the canonical autophagy machinery. Endonucleosis and hyperploidization are temporary, early events in the surviving Setd8-deficient cells. Larger vesicles break down into microvesicles over time and are eventually eliminated. The results reveal sequential events in cells with extensive DNA damage, which function as part of survival mechanisms to prevent necrotic death. Extensive cellular stress or DNA damage can alter nuclear morphology. Here, the authors show that cells lacking Setd8 or under metabolic stress internalize cytoplasmic material into the nucleus.