The EARP Complex and Its Interactor EIPR-1 Are Required for Cargo Sorting to Dense-Core Vesicles

PLoS Genet. 2016 May 18;12(5):e1006074. doi: 10.1371/journal.pgen.1006074. eCollection 2016 May.


The dense-core vesicle is a secretory organelle that mediates the regulated release of peptide hormones, growth factors, and biogenic amines. Dense-core vesicles originate from the trans-Golgi of neurons and neuroendocrine cells, but it is unclear how this specialized organelle is formed and acquires its specific cargos. To identify proteins that act in dense-core vesicle biogenesis, we performed a forward genetic screen in Caenorhabditis elegans for mutants defective in dense-core vesicle function. We previously reported the identification of two conserved proteins that interact with the small GTPase RAB-2 to control normal dense-core vesicle cargo-sorting. Here we identify several additional conserved factors important for dense-core vesicle cargo sorting: the WD40 domain protein EIPR-1 and the endosome-associated recycling protein (EARP) complex. By assaying behavior and the trafficking of dense-core vesicle cargos, we show that mutants that lack EIPR-1 or EARP have defects in dense-core vesicle cargo-sorting similar to those of mutants in the RAB-2 pathway. Genetic epistasis data indicate that RAB-2, EIPR-1 and EARP function in a common pathway. In addition, using a proteomic approach in rat insulinoma cells, we show that EIPR-1 physically interacts with the EARP complex. Our data suggest that EIPR-1 is a new interactor of the EARP complex and that dense-core vesicle cargo sorting depends on the EARP-dependent trafficking of cargo through an endosomal sorting compartment.

Publication types

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

MeSH terms

  • Animals
  • Biogenic Amines / metabolism
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Carrier Proteins / genetics*
  • Endosomes / genetics
  • Endosomes / metabolism
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Multiprotein Complexes / genetics
  • Mutation
  • Neurons / metabolism
  • Peptide Hormones / genetics
  • Proteomics
  • Secretory Vesicles / genetics*
  • Secretory Vesicles / metabolism
  • Synaptic Vesicles / genetics*
  • Synaptic Vesicles / metabolism
  • rab2 GTP-Binding Protein / genetics*
  • rab2 GTP-Binding Protein / metabolism


  • Biogenic Amines
  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • EIPR-1 protein, C elegans
  • Intercellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Peptide Hormones
  • rab2 GTP-Binding Protein