Department of Neuroscience, The Scripps Research Institute, Jupiter, FL.
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL
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.
隧道纳米管（TNT）是一种薄的、膜状的、管状的细胞间连接，但它们的生物发生或功能作用的机制仍然不清楚。在这里，我们报告了 Rhes，一种富含大脑的 GTPase/SUMO E3 样蛋白，通过它诱导 TNT 样细胞突起“Rhes 隧道”的生物发生，Rhes 通过这些隧道在细胞间移动，并运输亨廷顿病（HD）蛋白，即多聚 Q 扩展突变 Huntingtin（mHTT）。TNT 样 Rhes 隧道的形成需要 Rhes 的丝氨酸 33、C 端 CAAX 和 SUMO E3 样结构域。电子显微镜分析显示，TNT 样 Rhes 隧道呈连续的细胞间连接，直径<200nm。活细胞成像显示，Rhes 隧道与邻近细胞建立接触，并传递 Rhes 阳性货物，这些货物在进入邻近细胞之前穿过邻近细胞的质膜。Rhes 隧道携带 Rab5a/Lyso 20 阳性囊泡并运输 mHTT，但不运输正常 HTT、mTOR 或 wtTau 蛋白。SUMOylation 缺陷型 mHTT、Rhes C263S（不能 SUMOylate mHTT）或 CRISPR/Cas9 介导的三种 SUMO 同工型的耗竭会减少 Rhes 介导的 mHTT 运输。因此，Rhes 促进 TNT 样细胞突起的生物发生，并通过 SUMO 介导的机制促进 mHTT 的细胞间运输。
