CGAS

Phenotypes

Mouse phenotype:

decreased prepulse inhibition; abnormal tail movements; abnormal bone mineralization; decreased grip strength; increased startle reflex; increased lactate dehydrogenase level; decreased circulating amylase level; abnormal behavior

Ciliopathy associations

• Retinal Dystrophy/Degeneration

References: PMID:37217935

Subcellular localization

cytosol, nuclear bodies, nucleoplasm

References: PMID:40229503

Functional category

• Muscle contraction & physiology; Small GTPases; Ciliary assembly/disassembly; Cilia–cytoskeleton/adhesion links

Function

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(PMID: 40229503).