Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion

J Cell Biol. 2019 Jun 3;218(6):1972-1993. doi: 10.1083/jcb.201807068. Epub 2019 May 10.


Tunneling nanotubes (TNT) are thin, membranous, tunnel-like cell-to-cell connections, but the mechanisms underlying their biogenesis or functional role remains obscure. Here, we report, Rhes, a brain-enriched GTPase/SUMO E3-like protein, induces the biogenesis of TNT-like cellular protrusions, "Rhes tunnels," through which Rhes moves from cell to cell and transports Huntington disease (HD) protein, the poly-Q expanded mutant Huntingtin (mHTT). The formation of TNT-like Rhes tunnels requires the Rhes's serine 33, C-terminal CAAX, and a SUMO E3-like domain. Electron microscopy analysis revealed that TNT-like Rhes tunnels appear continuous, cell-cell connections, and <200 nm in diameter. Live-cell imaging shows that Rhes tunnels establish contact with the neighboring cell and deliver Rhes-positive cargoes, which travel across the plasma membrane of the neighboring cell before entering it. The Rhes tunnels carry Rab5a/Lyso 20-positive vesicles and transport mHTT, but not normal HTT, mTOR, or wtTau proteins. SUMOylation-defective mHTT, Rhes C263S (cannot SUMOylate mHTT), or CRISPR/Cas9-mediated depletion of three isoforms of SUMO diminishes Rhes-mediated mHTT transport. Thus, Rhes promotes the biogenesis of TNT-like cellular protrusions and facilitates the cell-cell transport of mHTT involving SUMO-mediated mechanisms.

Publication types

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

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Animals
  • Cell Communication*
  • Cell Surface Extensions / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Huntingtin Protein / metabolism*
  • Huntington Disease
  • Mice
  • Mice, Inbred C57BL
  • Nanotubes / chemistry*
  • Neurons / metabolism*
  • Protein Transport


  • Htt protein, mouse
  • Huntingtin Protein
  • GTP-Binding Proteins
  • Rasd2 protein, mouse