Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways

• Published in: Developmental cell Vol. 43; no. 6; pp. 744 - 762.e11
• Main Authors: Sigg, Monika Abedin, Menchen, Tabea, Lee, Chanjae, Johnson, Jeffery, Jungnickel, Melissa K., Choksi, Semil P., Garcia, Galo, Busengdal, Henriette, Dougherty, Gerard W., Pennekamp, Petra, Werner, Claudius, Rentzsch, Fabian, Florman, Harvey M., Krogan, Nevan, Wallingford, John B., Omran, Heymut, Reiter, Jeremy F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.12.2017
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; Cell Culture Techniques; Choanoflagellata - metabolism; choanoflagellate; Cilia - genetics; Cilia - metabolism; ciliopathy; cilium; GPCR; Hedgehog Proteins - metabolism; Hedgehog signaling; Humans; left-right axis patterning; Mice; Mutation; Organelles - metabolism; Phylogeny; proteomics; Proteomics - methods; Receptors, G-Protein-Coupled - metabolism; sea anemone; Sea Anemones - metabolism; sea urchin; Sea Urchins - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; Transient Receptor Potential Channels - metabolism; TRP channel; Xenopus laevis - metabolism; Zebrafish - metabolism; cilium; TRP channel; left-right axis patterning; proteomics; Hedgehog signaling; GPCR; sea urchin; sea anemone; choanoflagellate; ciliopathy
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.11.014

Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals. We demonstrated that candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein identified in the cilia of all three organisms. ENKUR localizes to motile cilia and is required for patterning the left-right axis in vertebrates. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to signaling, and uncovers a ciliary protein that underlies development and human disease. [Display omitted] •Evolutionary proteomics identifies conserved ciliary proteins•Ciliary regulators of Hh, GPCR, and TRP channel signaling evolved before bilateria•ENKUR localizes to motile cilia and is required for left-right axis patterning•Mutation of ENKUR causes situs inversus in humans Cilia are cellular appendages used for motility and intercellular communication. Sigg et al. reconstruct the evolutionary ancestry of cilia through proteomics of sea urchin, sea anemone, and choanoflagellate cilia. One identified ciliary protein, ENKUR, helps pattern the vertebrate left-right body axis. Humans with inherited mutations in ENKUR have situs inversus.