Evolutionary proteomics uncovers ciliary signaling components

Monika Abedin Sigg; Tabea Menchen; Jeffery Johnson; Chanjae Lee; Semil P. Choksi; Galo Garcia; Henriette Busengdal; Gerard Dougherty; Petra Pennekamp; Claudius Werner; Fabian Rentzsch; Nevan Krogan; John B. Wallingford; Heymut Omran; Jeremy F. Reiter

Xenopus and mouse nodal cells, sea anemone and sea urchin embryonic epithelial cells) and 524 those with multiple cilia (i.e., mouse tracheal epithelial cells, Xenopus embryonic epidermal 525 cells). In addition, ENKUR from animals and choanoflagellates localizes to cilia, raising the 526 possibility that it acts within cilia to generate or respond to fluid flow. Mutation of Enkur in the 527 mouse did not compromise ciliary beat frequency in tracheal epithelial cells, indicating that, 528 unlike many ciliary proteins with expression patterns and phylogenetic distributions similar to 529 ENKUR (e.g., outer arm dyneins), it is not essential for ciliary motility. Instead, ENKUR is 530 required for patterning of the left-right axis in both Xenopus and mouse, suggesting that it is 531 required for some aspect of ciliary beating or signaling in the embryonic node. Significantly, 532 humans with a homozygous mutation in ENKUR displayed inversion of their left-right axis, but 533 no signs of defective mucociliary clearance, suggesting that human ENKUR loss of function does 534 not cause PCD, but may be a cause situs inversus. 535 ENKUR has previously been shown to interact with TRP channels and calcium signaling 536 proteins, suggesting that it may bridge the gap between TRP channels and downstream signaling 537 The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/153437 doi: bioRxiv preprint (Tisler et al., 2016; Warner et al., 2016 ). PKD2 has also been shown to be expressed in the 544 ciliary tuft of sea urchin embryos, a structure hypothesized to have sensory function (Tisler et al., 545 2016) . We found that, like PKD2, Enkur mRNA is enriched in the cells of both the sea urchin 546 and sea anemone ciliary tuft. It will be of great interest to assess whether ENKUR regulates or 547 interprets calcium responses in nodal, archenteron or tuft cilia. 548