Stiff matrix-induced KRTAP2-3 expression suppresses ciliogenesis via actin tension-driven chromatin remodeling

Abstract Primary cilia are sensory organelles that project from the cell surface and play vital roles in cell signaling pathways essential for development and homeostasis. However, the mechanotransduction pathways through which cells perceive and respond to matrix rigidity to regulate ciliogenesis remain poorly understood. In this study, we find that increased matrix stiffness significantly reduces primary cilia formation compared to soft matrix. Disruption of actin polarization of cells on stiff matrix restores ciliation, indicating the actin cytoskeleton as a pivotal transducer of mechanical signals in this process. RNA sequencing identifies significant upregulation of KRTAP2-3 (keratin-associated protein 2-3) mRNA in cells on stiff matrix. Functional assays reveal that knockdown of KRTAP2 - 3 reverses the stiffness-induced inhibition of ciliogenesis. Additionally, actin polarization on stiff matrix promotes KRTAP2-3 expression, thereby inhibiting cilia formation. Further mechanistic studies show that actin cytoskeleton tension induces nuclear deformation and alters nuclear architecture, thereby enhancing chromatin accessibility at the KRTAP2-3 gene locus, which leads to the activation of KRTAP2-3 transcription. Collectively, these results suggest a previously unrecognized mechanotransduction pathway in which matrix stiffness drives actin cytoskeleton tension-dependent nuclear deformation, chromatin remodeling, and upregulation of KRTAP2-3 , ultimately leading to the suppression of ciliogenesis.