An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability

Nat Commun. 2014 Oct 3;5:4904. doi: 10.1038/ncomms5904.

Abstract

Neuropilins (NRPs) are trans-membrane receptors involved in axon guidance and vascular development. Many growth factors and other signalling molecules bind to NRPs through a carboxy (C)-terminal, basic sequence motif (C-end Rule or CendR motif). Peptides with this motif (CendR peptides) are taken up into cells by endocytosis. Tumour-homing CendR peptides penetrate through tumour tissue and have shown utility in enhancing drug delivery into tumours. Here we show, using RNAi screening and subsequent validation studies, that NRP1-mediated endocytosis of CendR peptides is distinct from known endocytic pathways. Ultrastructurally, CendR endocytosis resembles macropinocytosis, but is mechanistically different. We also show that nutrient-sensing networks such as mTOR signalling regulate CendR endocytosis and subsequent intercellular transport of CendR cargo, both of which are stimulated by nutrient depletion. As CendR is a bulk transport pathway, our results suggest a role for it in nutrient transport; CendR-enhanced drug delivery then makes use of this natural pathway.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Drug Delivery Systems
  • Endocytosis*
  • Food
  • Gold / chemistry
  • HeLa Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Ligands
  • Male
  • Metal Nanoparticles / chemistry
  • Mice
  • Microscopy, Fluorescence
  • Neoplasm Transplantation
  • Neuropilin-1 / physiology*
  • Peptides / chemistry
  • Pinocytosis
  • Protein Structure, Tertiary
  • RNA Interference
  • Silver / chemistry

Substances

  • Ligands
  • Peptides
  • Neuropilin-1
  • Silver
  • Gold