title: Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis.
abstract: The cilium both releases and binds to extracellular vesicles (EVs). EVs may be used by cells as a form of intercellular communication and mediate a broad range of physiological and pathological processes. The mammalian polycystins (PCs) localize to cilia, as well as to urinary EVs released from renal epithelial cells. PC ciliary trafficking defects may be an underlying cause of autosomal dominant polycystic kidney disease (PKD), and ciliary-EV interactions have been proposed to play a central role in the biology of PKD. In Caenorhabditis elegans and mammals, PC1 and PC2 act in the same genetic pathway, act in a sensory capacity, localize to cilia, and are contained in secreted EVs, suggesting ancient conservation. However, the relationship between cilia and EVs and the mechanisms generating PC-containing EVs remain an enigma. In a forward genetic screen for regulators of C. elegans PKD-2 ciliary localization, we identified CIL-7, a myristoylated protein that regulates EV biogenesis. Loss of CIL-7 results in male mating behavioral defects, excessive accumulation of EVs in the lumen of the cephalic sensory organ, and failure to release PKD-2::GFP-containing EVs to the environment. Fatty acylation, such as myristoylation and palmitoylation, targets proteins to cilia and flagella. The CIL-7 myristoylation motif is essential for CIL-7 function and for targeting CIL-7 to EVs. C. elegans is a powerful model with which to study ciliary EV biogenesis in vivo and identify cis-targeting motifs such as myristoylation that are necessary for EV-cargo association and function.
authors.affiliation: Department of Genetics and Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Maguire
authors.affiliation: Department of Genetics and Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854.
authors.forename: Malan
authors.initials: M
authors.lastname: Silva
authors.affiliation: Center for C. elegans Anatomy, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Ken C Q
authors.initials: KC
authors.lastname: Nguyen
authors.affiliation: Department of Genetics and Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hellen
authors.affiliation: Department of Genetics and Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Kern
authors.affiliation: Center for C. elegans Anatomy, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: David H
authors.initials: DH
authors.lastname: Hall
authors.affiliation: Department of Genetics and Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854 barr@dls.rutgers.edu.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Barr
mesh_terms: D000215:Acylation; D000818:Animals; D001692:Biological Transport; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D009226:Myristates / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000378:metabolism; D050396:TRPP Cation Channels / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D009226:Myristates; D050396:TRPP Cation Channels