State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Reproductive Physiology Laboratory, National Research Institute for Family Planning, Beijing, China.
Andrologia. 2022 Apr;54(3):e14350. doi: 10.1111/and.14350. Epub 2021 Dec 13.
Activating transcription factor 6 (ATF6), also known as ACHM7, ATF6A, encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. It functions as nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is presented in the promoters of genes encoding ER chaperones. Studies have shown that endoplasmic reticulum stress (ERS) can cause damage to spermatozoa and testes, leading to male sterility. And we find that the expression of ATF6 in spermatozoa of some infertile patients is significantly reduced. Then, we construct the Atf6 knockout mice model and interestingly find a decline in male fertility. The downstream gene testis-specific serine/threonine-protein kinase 4 (Tssk4) is screened based on transcriptome sequencing. We use Western blot and real-time PCR to confirm this result in both 293T cells and Atf6 knockout mice. TSSK4 is essential in male germ cell genesis and sperm maturation. Our results suggest that the expression of TSSK4 may be regulated by ATF6. The effect of Atf6 knockout on the reproductive development of male mice may be related to the low expression of TSSK4, which further verify that there may be some relationship between ERS and male reproduction.
激活转录因子 6（ATF6），也称为 ACHM7、ATF6A，编码一种转录因子，在内质网（ER）应激期间激活未折叠蛋白反应（UPR）的靶基因。它通过内质网应激反应元件（ERSE）发挥核转录因子的作用，该元件存在于编码内质网伴侣的基因启动子中。研究表明，内质网应激（ERS）可导致精子和睾丸损伤，导致男性不育。我们发现，一些不育患者精子中的 ATF6 表达显著降低。然后，我们构建了 Atf6 敲除小鼠模型，有趣的是发现雄性生育力下降。基于转录组测序筛选下游基因睾丸特异性丝氨酸/苏氨酸蛋白激酶 4（Tssk4）。我们使用 Western blot 和实时 PCR 在 293T 细胞和 Atf6 敲除小鼠中验证了这一结果。TSSK4 在雄性生殖细胞发生和精子成熟中是必不可少的。我们的结果表明，TSSK4 的表达可能受到 ATF6 的调控。Atf6 敲除对雄性小鼠生殖发育的影响可能与 TSSK4 的低表达有关，这进一步验证了 ERS 与男性生殖之间可能存在某些关系。
