Conserved machinery, divergent functions: evolutionary plasticity of the STK36/ULK4 kinase complex in ciliogenesis and signaling

The cilium is an ancient organelle in eukaryotes essential for motility, sensory perception, and signaling, and ciliary dysfunction underlies a spectrum of human ciliopathies. In this context, the STK36/ULK4 kinase complex has emerged as a conserved molecular machinery critical for motile ciliogenesis. Fused (Fu, STK36 ortholog), first characterized in Drosophila as a regulator of Hedgehog (Hh) signaling, is a serine/threonine kinase conserved across eukaryotic lineages, yet exhibits functional divergence. While crucial for the Hh pathway in insects and teleosts, it is dispensable for Hh signaling yet essential for ciliary assembly in mammals. Accumulating evidence shows that STK36 and ULK4 form a complex that plays an ancestral role in ciliogenesis, with functions traceable to flagellated protists and implications in the human ciliopathy, primary ciliary dyskinesia (PCD). This suggests that the ancestral role of STK36 is rooted in ciliogenesis, while its incorporation into the Hh pathway in insects and teleosts represents lineage-specific adaptations. This review consolidates genetic, biochemical, and cell biological studies to provide an integrated perspective on STK36/ULK4 function. Given its implication in human motile ciliopathies, further investigation will not only clarify its evolutionary history but may also yield therapeutic insights into PCD.