HUWE1 is a HECT-domain ubiquitin E3 ligase expressed in various tissues. Although HUWE1 is known to promote degradation of the tumor suppressor p53, given a growing list of its substrates, in vivo functions of HUWE1 remain elusive. Here, we investigated the role of HUWE1 in the female reproductive system. Homozygous deletion of Huwe1 in mouse oocytes of primary follicles caused oocyte death and female infertility, whereas acute depletion of HUWE1 protein by Trim-Away technology did not impact oocytes from antral follicles. Interestingly, oocytes from Huwe1 heterozygous females matured and fertilized normally, but the majority of embryos that lacked maternal Huwe1 were arrested at the morula stage after fertilization. Consequently, Huwe1 heterozygous females only produced wild-type pups. Concomitant knockout of p53 did not recover fertility of the Huwe1 knockout females. These findings make HUWE1 a unique and critical maternal factor indispensable for maintaining the quality of oocytes and embryos.

HUWE1 是一种 HECT 结构域泛素 E3 连接酶，在多种组织中表达。尽管已知 HUWE1 可以促进肿瘤抑制因子 p53 的降解，但考虑到其底物的数量不断增加， HUWE1 的体内功能仍然难以捉摸。在这里，我们研究了 HUWE1 在女性生殖系统中的作用。小鼠初级卵母细胞中Huwe1的纯合缺失会导致卵母细胞死亡和女性不孕，而通过 Trim-Away 技术急性去除 HUWE1 蛋白不会影响窦卵母细胞。有趣的是，来自Huwe1杂合雌性的卵母细胞正常成熟并受精，但大多数缺乏母本Huwe1的胚胎在受精后被停滞在桑葚胚阶段。因此，Huwe1杂合雌性仅产生野生型幼崽。同时敲除p53并没有恢复Huwe1敲除雌性的生育能力。这些发现使 HUWE1 成为维持卵母细胞和胚胎质量不可或缺的独特而关键的母体因子。