A Lipid Receptor Sorts Polyomavirus from the Endolysosome to the Endoplasmic Reticulum to Cause Infection

The mechanisms by which receptors guide intracellular virus transport are poorly characterized. The murine polyomavirus (Py) binds to the lipid receptor ganglioside GD1a and traffics to the endoplasmic reticulum (ER) where it enters the cytosol and then the nucleus to initiate infection. How Py reaches the ER is unclear. We show that Py is transported initially to the endolysosome where the low pH imparts a conformational change that enhances its subsequent ER-to-cytosol membrane penetration. GD1a stimulates not viral binding or entry, but rather sorting of Py from late endosomes and/or lysosomes to the ER, suggesting that GD1a binding is responsible for ER targeting. Consistent with this, an artificial particle coated with a GD1a antibody is transported to the ER. Our results provide a rationale for transport of Py through the endolysosome, demonstrate a novel endolysosome-to-ER transport pathway that is regulated by a lipid, and implicate ganglioside binding as a general ER targeting mechanism.

受体介导细胞内病毒运输的具体机制目前尚未得到充分阐明。鼠多瘤病毒（murine polyomavirus, Py）可结合脂质受体神经节苷脂GD1a（ganglioside GD1a），并被转运至内质网（endoplasmic reticulum, ER），随后侵入胞质溶胶并进入细胞核以启动感染过程。目前学界尚不明确Py抵达内质网的具体途径。本研究证实，Py最初会被转运至内溶酶体（endolysosome），其内的低pH环境可诱导病毒发生构象改变，增强其后续从内质网向胞质溶胶的膜穿透能力。GD1a并非调控病毒的吸附或侵入过程，而是介导Py从晚期内体和/或溶酶体向内质网的分选转运，这提示GD1a结合事件负责介导病毒的内质网靶向。与此结论一致的是，经GD1a抗体包被的人工颗粒同样可被转运至内质网。本研究结果为Py通过内溶酶体的运输通路提供了理论依据，揭示了一条受脂质调控的全新内溶酶体-内质网转运途径，并证实神经节苷脂结合可作为一种通用的内质网靶向机制。