AKAP2/PKA complex coordinates primary ciliogenesis, ciliary trafficking and Shh signaling.

The primary cilium is a sensory organelle present in all eukaryotic cells that acts as a signaling hub that receives, integrates and transmits signals carried out by extracellular stimuli, playing a fundamental role in cell behavior, development and tissue homeostasis. Genetic mutations in genes encoding for structural components and regulators of primary cilium underlie severe developmental defects, also known as ciliopathies. Understanding cilium biology may, thus, provide novel therapeutic strategies for ciliopathies. Here, we report that A-Kinase Anchor protein 2(AKAP2) dynamically localizes within the primary cilium and forms complexes with kinesin motor proteins and components of the intra-flagellar transport system. Genetic deletion experiments and functional analysis demonstrate that AKAP2/PKA complex controls cilium biogenesis and intraciliary trafficking of cargo receptors, acting as a positive regulator of Shh pathway. In the medaka fish model, depletion of AKAP2 affects ciliogenesis and ciliary trafficking, delays embryonic development and significantly increases the embryonic death rate.Our findings identify AKAP2 as a ciliary scaffold protein that finely controls ciliogenesis, intraciliary trafficking and Hedgehog signaling cascade. Manipulating ciliary AKAP2 signaling, thus, provides a new therapeutic window for ciliopathy disorders.