Li Bo, He Yu-Ying, Yao Wen-Xu, Jin Dan-Dan, Luo Hui-Na, Li Meng-Yuan, Wu Ying, Yang Zeng-Ming
Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang, 550025, China.
College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
Commun Biol. 2025 Apr 14;8(1):607. doi: 10.1038/s42003-025-08030-x.
Primary cilia are antenna-like organelles that sense extracellular signals and function as signaling hubs essential for vertebrate development and homeostasis. Decidualization is crucial for pregnancy establishment and maintenance in both humans and mice. While primary cilia are present in endometrial stromal cells, their role in pregnancy remains unknown. Here, we identify TMEM67, a key component of the ciliary transition zone, as a critical regulator of mouse decidualization. Loss of primary cilia triggers RhoA-MLC2-dependent actomyosin contraction, which transmits mechanical forces to the nuclear lamina, leading to micronuclei formation. Within these micronuclei, double-stranded DNA (dsDNA) can directly bind to cyclic GMP-AMP synthase (cGAS) in situ, initiating downstream signaling. This activation of the cGAS-STING pathway reduces CCL6 production and impairs decidualization. Furthermore, pharmacological inhibition of actin polymerization or RhoA-ROCK signaling alleviates mechanical forces surrounding stromal cells, restores ciliogenesis, maintains nuclear integrity, suppresses the cGAS-STING pathway activation, and ultimately rescues decidualization. Our findings reveal a previously unrecognized mechanism by which primary cilia regulate the actin cytoskeleton to maintain nuclear integrity and prevent DNA leakage. This safeguards against aberrant activation of the cGAS-STING pathway, which would otherwise trigger detrimental immune signaling and impair decidualization.
初级纤毛是天线状细胞器，可感知细胞外信号，并作为脊椎动物发育和体内平衡所必需的信号枢纽发挥作用。蜕膜化对于人类和小鼠的妊娠建立和维持至关重要。虽然初级纤毛存在于子宫内膜基质细胞中，但其在妊娠中的作用仍不清楚。在这里，我们确定纤毛过渡区的关键成分跨膜蛋白67（TMEM67）是小鼠蜕膜化的关键调节因子。初级纤毛的缺失会触发RhoA-肌球蛋白轻链2（MLC2）依赖性的肌动球蛋白收缩，将机械力传递至核纤层，导致微核形成。在这些微核内，双链DNA（dsDNA）可直接原位结合环状GMP-AMP合酶（cGAS），启动下游信号传导。cGAS-干扰素基因刺激蛋白（STING）途径的这种激活会减少趋化因子6（CCL6）的产生并损害蜕膜化。此外，肌动蛋白聚合或RhoA-ROCK信号传导的药理学抑制可减轻基质细胞周围的机械力，恢复纤毛发生，维持核完整性，抑制cGAS-STING途径的激活，并最终挽救蜕膜化。我们的研究结果揭示了一种以前未被认识的机制，通过该机制初级纤毛调节肌动蛋白细胞骨架以维持核完整性并防止DNA泄漏。这可防止cGAS-STING途径的异常激活，否则会触发有害的免疫信号并损害蜕膜化。
