Regulation and function of inosine monophosphate dehydrogenase 2 cytoophidia during mouse and human decidualization

Decidualization is essential for establishing pregnancy in both mice and humans. Cellular stresses, including nucleolar stress and DNA damage, are involved in this process. Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for de novo guanosine triphosphate (GTP) synthesis, forms membrane-free macromolecular structures called "cytoophidia" under specific conditions. However, whether IMPDH cytoophidia are present during decidualization remains unknown. In this study, we found that IMPDH2 cytoophidia are primarily detected in mouse decidual cells during early pregnancy. On day 5 of pregnancy, more IMPDH2 cytoophidia are observed at implantation sites than at inter-implantation sites. Physiologically, uteri activated by estrogen exhibit more IMPDH2 cytoophidia than those maintained in a delayed state by progesterone. Although GTP is required for in vitro decidualization in mice, elevated GTP level impairs this process. Furthermore, IMPDH2 cytoophidia can induce nucleolar stress and DNA damage in mice. In the human endometrium, IMPDH2 cytoophidia are observed during the menstrual cycle, particularly enriched in the secretory phase. They promote human decidualization and naturally enhance cellular senescence. Our findings highlight the physiological relevance of IMPDH2 cytoophidia during early pregnancy in mice and humans.