WNK1 regulates uterine homeostasis and its ability to support pregnancy
WNK1 regulates uterine homeostasis and its ability to support pregnancy
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DOI：
10.1172/jci.insight.141832
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发表时间：
2020-11-19
期刊：
影响因子：
8
通讯作者：
DeMayo, Francesco J.
中科院分区：
文献类型：
--
作者：
Chi, Ru-pin Alicia;Wang, Tianyuan;DeMayo, Francesco J.
WNK 1（不含赖氨酸[K]激酶1）是一种在人类和小鼠中广泛表达的非典型激酶蛋白。其编码基因的突变导致人类高血压，这与异常离子稳态有关。WNK 1对人子宫内膜间质细胞的体外蜕膜化至关重要，从而证明其在女性生殖中的重要性。使用小鼠模型，在雌性生殖道中消融WNK 1，以确定其在子宫生物学中的体内作用。WNK 1的缺失改变了子宫形态，导致子宫内膜上皮增生、腺肌症特征和胚胎着床延迟，最终导致生育能力受损。结合转录组学，蛋白质组学和interactomic分析揭示了一个潜在的新的调节途径，WNK 1抑制AKT磷酸化通过蛋白磷酸酶2A（PP2A）在子宫内膜细胞从人类和小鼠。我们发现WNK 1与PPP2R1A相互作用，PP2A支架亚基的α亚型。这维持了PP2A亚基的水平并稳定了其活性，然后使AKT去磷酸化。因此，WNK 1的缺失降低了PP2A活性，导致AKT信号过度。使用FOXO 1作为AKT活性的读数，我们证明了FOXO 1磷酸化和核排斥的升级，导致对胚胎着床至关重要的基因表达的中断。
WNK1 (with no lysine [K] kinase 1) is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans, which is associated with abnormal ion homeostasis. WNK1 is critical for in vitro decidualization in human endometrial stromal cells, thereby demonstrating its importance in female reproduction. Using a mouse model, WNK1 was ablated in the female reproductive tract to define its in vivo role in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyotic features, and a delay in embryo implantation, ultimately resulting in compromised fertility. Combining transcriptomic, proteomic, and interactomic analyses revealed a potentially novel regulatory pathway whereby WNK1 represses AKT phosphorylation through protein phosphatase 2A (PP2A) in endometrial cells from both humans and mice. We show that WNK1 interacted with PPP2R1A, the alpha isoform of the PP2A scaffold subunit. This maintained the levels of PP2A subunits and stabilized its activity, which then dephosphorylated AKT. Therefore, loss of WNK1 reduced PP2A activity, causing AKT hypersignaling. Using FOXO1 as a readout of AKT activity, we demonstrate that there was escalated FOXO1 phosphorylation and nuclear exclusion, leading to a disruption in the expression of genes that are crucial for embryo implantation.