Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways

Dev Cell. 2017 Dec 18;43(6):744-762.e11. doi: 10.1016/j.devcel.2017.11.014.

Abstract

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.

Keywords: GPCR; Hedgehog signaling; TRP channel; choanoflagellate; ciliopathy; cilium; left-right axis patterning; proteomics; sea anemone; sea urchin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism*
  • Cell Culture Techniques
  • Choanoflagellata / metabolism
  • Cilia / genetics*
  • Cilia / metabolism*
  • Hedgehog Proteins / metabolism
  • Humans
  • Mice
  • Mutation
  • Organelles / metabolism
  • Phylogeny
  • Proteomics / methods
  • Receptors, G-Protein-Coupled / metabolism
  • Sea Anemones / metabolism
  • Sea Urchins / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transient Receptor Potential Channels / metabolism
  • Xenopus laevis / metabolism
  • Zebrafish / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Calmodulin-Binding Proteins
  • ENKUR protein, human
  • Hedgehog Proteins
  • Receptors, G-Protein-Coupled
  • Transient Receptor Potential Channels