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.

Lipid-Mediated Endocytosis

“…3). Interestingly, when quantum dots are functionalized either with GD1a antibodies or cholera toxin, they are not recycled like ganglioside antibodies or transported to the Golgi apparatus like cholera toxin, but sorted to the ER, suggesting that the three-dimensional organization of binding site on colloids may play a role in intracellular sorting (Tekle et al 2008;Qian et al 2009). A similar clustering dependent defect of trafficking to the Golgi has been observed for ricin (van Deurs et al 1986).…”

“…However, this is preceded by slow passage through endocytic compartments (Liebl et al 2006;Qian et al 2009;Engel et al 2011). The first station in the entry of mPy and SV40 seems to be the EE followed by either the RE or LE and endolysosomes.…”

“…The first station in the entry of mPy and SV40 seems to be the EE followed by either the RE or LE and endolysosomes. Eventually, from these endocytic organelles, the viruses move by poorly defined mechanisms to the ER (Kartenbeck et al 1989;Qian et al 2009). For mPy and SV40, the best characterized of the polyoma viruses, the transport is slow.…”

How Viruses Use the Endoplasmic Reticulum for Entry, Replication, and Assembly

“…After internalization, the virus is transferred first to the endolysosome (Eash et al 2004;Querbes et al 2006;Qian et al 2009;Engel et al 2011) and then the ER Gilbert and Benjamin 2004;Qian et al 2009). Py transport to the ER, a phenomenon documented over 20 years ago by Helenius and coworkers using electron microscopy (EM) (Kartenbeck et al 1989), is unique as most extracellular ligands do not reach the ER after endocytosis.…”

Molecular Signaling and Cellular Pathways for Virus Entry

“…e cell endocytic mechanism also provides a route for virus internalization. Recent research has discovered that numerous viruses favor the endocytosis as clathrin-mediated endocytosis (CME) [2][3][4][5][6][7], caveolae/lipid ra-mediated endocytosis [8][9][10], macropinocytosis [11][12][13], and several other unusual pathways [14,15] by eliciting the endocytic signaling pathways. is review focuses on the elements that are involved in regulating the mechanism of virus entry and their traffic systems.…”