Journal
JOURNAL OF CELL BIOLOGY
Volume 218, Issue 6, Pages 1972-1993Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201807068
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Funding
- Lottie French Lewis Fund of the Community Foundation for Palm Beach and Martin Counties
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01-NS087019-01A1, R01-NS094577-01A1]
- Cure Huntington Disease Initiative (CHDI) foundation
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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.
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