Bhatia Priyankaa, Tafur Judith, Amin Ruchi, Familiari Nicole E, Yaguchi Kan, Tran Vanna M, Bond Alec, Bukulmez Orhan, Woodruff Jeffrey B
Department of Cell Biology, Department of Biophysics, UT Southwestern Medical Center, Dallas, TX, USA.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, TX, USA.
Life Sci Alliance. 2025 May 29;8(8). doi: 10.26508/lsa.202503387. Print 2025 Aug.
Animals store oocytes in a dormant state for weeks to decades before ovulation. The homeostatic programs that oocytes use to endure long-term storage are poorly understood. Using female nematodes as a short-lived model, we found that oocyte formation and storage required IFET-1, the conserved eIF4E-transporter protein (eIF4ET). IFET-1 co-assembled with CAR-1 (Lsm14) to form micron-scale condensates in stored oocytes, which dissipated after oocyte activation. Depletion of IFET-1 destabilized the stored oocyte proteome, leading to lower translation, a decline in microtubule maintenance proteins, and errors in microtubule organization and meiotic spindle assembly. Deleting domains within IFET-1 impaired oocyte storage without affecting oocyte formation. Thus, in addition to establishing a healthy oocyte reserve in young mothers, IFET-1 ensures that correct levels of cytoskeletal proteins are maintained as oocytes age. eIF4ET also localized to micron-scale puncta in dormant human oocytes. Our results clarify how eIF4ET maintains the oocyte reserve and further support eIF4ET dysfunction as an upstream cause of embryonic aneuploidy and age-related infertility.
动物在排卵前将卵母细胞以休眠状态储存数周甚至数十年。卵母细胞用于长期储存的稳态程序目前还知之甚少。我们以雌性线虫作为寿命较短的模型,发现卵母细胞的形成和储存需要IFET-1,即保守的真核起始因子4E转运蛋白(eIF4ET)。IFET-1与CAR-1(Lsm14)共同组装,在储存的卵母细胞中形成微米级的凝聚物,卵母细胞激活后这些凝聚物会消散。IFET-1的缺失使储存的卵母细胞蛋白质组不稳定,导致翻译水平降低、微管维持蛋白减少,以及微管组织和减数分裂纺锤体组装出现错误。删除IFET-1内的结构域会损害卵母细胞的储存,但不影响卵母细胞的形成。因此,IFET-1除了在年轻母亲体内建立健康的卵母细胞储备外,还能确保随着卵母细胞老化维持正确水平的细胞骨架蛋白。eIF4ET也定位于休眠人类卵母细胞中的微米级斑点。我们的研究结果阐明了eIF4ET如何维持卵母细胞储备,并进一步支持eIF4ET功能障碍是胚胎非整倍体和年龄相关不孕的上游原因。