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

Abstract

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.

Author Summary

To cause infection, viruses must reach appropriate compartments within the cell where they undergo a programmed series of conformational changes that enable the viral genome to be exposed and released. The mechanisms that target viruses to these compartments are often not clear. Here we study the infectious pathway of the murine polyomavirus (Py). Py is transported from the cell surface to the intracellular organelle called the endoplasmic reticulum (ER), where it breaches the ER membrane to reach the nucleus to stimulate infection. How Py is transported from the cell surface to the ER is poorly characterized. Our studies show that Py first enters the endolysosome compartments before reaching the ER. The low pH of the endolysosome imparts a structural change on the virus that facilitates its subsequent ER membrane penetration. Importantly, transport of Py from the endolysosome to the ER is guided by the lipid receptor ganglioside GD1a. We also demonstrate that an artificial bead capable of binding to GD1a is transported to the ER as well. Collectively, our data identify a lipid-dependent mechanism that targets a virus to its appropriate organelle during infection.