Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation

PLoS One. 2015 Jul 28;10(7):e0133966. doi: 10.1371/journal.pone.0133966. eCollection 2015.

Abstract

ADAMTS9 is a metalloprotease that cleaves components of the extracellular matrix and is also implicated in transport from the endoplasmic reticulum (ER) to the Golgi. It has been reported that an ADAMTS9 gene variant is associated with type 2 diabetes. The underlying pathology of type 2 diabetes is insulin resistance and beta-cell dysfunction. However, the molecular mechanisms underlying ADAMTS9 function in beta cells and peripheral tissues are unknown. We show that loss of C. elegans GON-1, an ADAMTS9 homolog, alters lifespan and dauer formation. GON-1 loss impairs secretion of proteins such as insulin orthologs and TGF-beta, and additionally impacts insulin/IGF-1 signaling in peripheral tissues. The function of the GON domain, but not the protease domain, is essential for normal lifespan and dauer formation in these scenarios. We conclude that the GON domain is critical for ADAMTS9/GON-1 function across species, which should help the understanding of type 2 diabetes in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • Animals
  • Animals, Genetically Modified / genetics
  • Animals, Genetically Modified / growth & development*
  • Animals, Genetically Modified / metabolism
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Golgi Apparatus / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Larva / growth & development*
  • Larva / metabolism
  • Longevity / physiology*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Insulin
  • ADAM Proteins
  • GON-1 protein, C elegans
  • Metalloendopeptidases

Grant support

This work was supported partly by the Program for Promoting the Establishment of Strategic Research Centers; Special Coordination Funds for Promoting Science and Technology; Ministry of Education, Culture, Sports, Science, and Technology (Japan) (to S.M.), a grant from the Uehara Memorial Foundation (to S.M.), and grant-in-Aid for young scientists from Japan Society for the promotion of Science (to S.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.