Primary cilia prevent activation of the cGAS-STING pathway during mouse decidualization

Area of Science:

• Cell Biology
• Reproductive Biology
• Organelle Function

Background:

• Primary cilia are crucial signaling hubs for development and homeostasis.
• Decidualization is essential for successful pregnancy.
• The role of primary cilia in endometrial stromal cells during pregnancy was unknown.

Purpose of the Study:

• To investigate the role of primary cilia in mouse decidualization.
• To identify key regulators of primary cilia function in this process.
• To elucidate the molecular mechanisms linking cilia to decidualization.

Main Methods:

• Utilized mouse models with genetic alterations affecting primary cilia.
• Investigated the impact of cilia loss on actomyosin cytoskeleton and nuclear integrity.
• Analyzed the activation of the cyclic GMP-AMP synthase (cGAS)-STING pathway.
• Employed pharmacological interventions to modulate cytoskeletal and signaling pathways.

Main Results:

• TMEM67, a ciliary transition zone protein, is critical for decidualization.
• Loss of primary cilia leads to actomyosin contraction, nuclear lamina damage, and micronuclei formation.
• DNA leakage into micronuclei activates the cGAS-STING pathway, reducing CCL6 and impairing decidualization.
• Inhibition of actin or RhoA-ROCK signaling rescues ciliogenesis, nuclear integrity, and decidualization.

Conclusions:

• Primary cilia maintain nuclear integrity by regulating the actin cytoskeleton.
• Preventing DNA leakage through intact cilia is crucial for suppressing aberrant cGAS-STING pathway activation.
• This mechanism highlights a novel link between primary cilia, nuclear stability, and immune signaling in pregnancy.