Abstract
Peptide-based intercellular communication is a ubiquitous and ancient process that predates evolution of the nervous system. Cilia are essential signaling centers that both receive information from the environment and secrete bioactive extracellular vesicles (ectosomes). However, the nature of these secreted signals and their biological functions remain poorly understood. Here, we report the developmentally regulated release of the peptide amidating enzyme, peptidylglycine α-amidating monooxygenase (PAM), and the presence of peptidergic signaling machinery (including propeptide precursors, subtilisin-like prohormone convertases, amidated products, and receptors) in ciliary ectosomes from the green alga Chlamydomonas. One identified amidated PAM product serves as a chemoattractant for mating-type minus gametes but repels plus gametes. Thus, cilia provide a previously unappreciated route for the secretion of amidated signaling peptides. Our study in Chlamydomonas and the presence of PAM in mammalian cilia suggest that ciliary ectosome-mediated peptidergic signaling dates to the early eukaryotes and plays key roles in metazoan physiology.
Highlights
Our understanding of peptidergic signaling grew out of studies on peptides like vasopressin, whose storage in nerve terminals facilitated its purification [1]; opioid peptides, which were identified based on their ability to interact with specific G protein–coupled receptors (GPCRs) [2]; and insulin, whose loss causes diabetes mellitus [3]
Subtilisin-like proteases cleave the propeptides into smaller products, many of which are subjected to posttranslational modification as they move through the Golgi complex and into secretory granules [3,4,5]
All of the components needed for the production of secreted signaling peptides are present in C. reinhardtii even though secretory granules, which are used to store bioactive peptides in species as diverse as Trichoplax, Drosophila, and humans, have not been observed
Summary
Our understanding of peptidergic signaling grew out of studies on peptides like vasopressin, whose storage in nerve terminals facilitated its purification [1]; opioid peptides, which were identified based on their ability to interact with specific G protein–coupled receptors (GPCRs) [2]; and insulin, whose loss causes diabetes mellitus [3]. Production of these signaling molecules begins in the endoplasmic reticulum, with synthesis of a prepropeptide. Based on extensive studies of peptidergic signaling in diverse metazoan invertebrates such as Drosophila, Caenorhabditis elegans, sea urchins, and placozoans, it is clear that the proteins
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