Abstract
Inhibitors of endosome acidification or cathepsin proteases attenuated infections mediated by envelope proteins of xenotropic murine leukemia virus-related virus (XMRV) and Ebola virus, as well as ecotropic, amphotropic, polytropic, and xenotropic murine leukemia viruses (MLVs), indicating that infections by these viruses occur through acidic endosomes and require cathepsin proteases in the susceptible cells such as TE671 cells. However, as previously shown, the endosome acidification inhibitors did not inhibit these viral infections in XC cells. It is generally accepted that the ecotropic MLV infection in XC cells occurs at the plasma membrane. Because cathepsin proteases are activated by low pH in acidic endosomes, the acidification inhibitors may inhibit the viral infections by suppressing cathepsin protease activation. The acidification inhibitors attenuated the activities of cathepsin proteases B and L in TE671 cells, but not in XC cells. Processing of cathepsin protease L was suppressed by the acidification inhibitor in NIH3T3 cells, but again not in XC cells. These results indicate that cathepsin proteases are activated without endosome acidification in XC cells. Treatment with an endocytosis inhibitor or knockdown of dynamin 2 expression by siRNAs suppressed MLV infections in all examined cells including XC cells. Furthermore, endosomal cathepsin proteases were required for these viral infections in XC cells as other susceptible cells. These results suggest that infections of XC cells by the MLVs and Ebola virus occur through endosomes and pH-independent cathepsin activation induces pH-independent infection in XC cells.
Highlights
Murine leukemia viruses (MLVs) are divided into four groups according to their host ranges
To test whether endosome acidification is required for the Ecotropic MLV (Eco-MLV) infection in XC cells, we monitored the effects of concanamycin A (ConA) and bafilomycin A-1 (BFLA-1) on this process
Mouse NIH3T3, rat XC, and human TE671 cells expressing the Eco-MLV receptor (TE671/mCAT1) [14] were pretreated with the inhibitors for 5 h, and were inoculated with the Eco- or VSVpseudotyped MLV vector diluted with fresh medium in absence of the inhibitor to minimize the effects on other steps of the MLV vector infection than entry
Summary
Murine leukemia viruses (MLVs) are divided into four groups according to their host ranges. Ecotropic MLV (Eco-MLV) infects mouse and rat cells. Amphotropic MLV (Ampho-MLV) infects many types of mammals including mouse, rat, mink, and human. The Eco- and Ampho-MLVs recognize cationic amino acid transporter 1 (CAT1) [1] and phosphate symporter 2 (Pit2) [2,3,4] as the infection receptors, respectively. Polytropic (Poly-) and xenotropic (Xeno-) MLVs both utilize the cell surface receptor protein XPR as the infection receptor [5,6,7]. The Poly- and Xeno-MLVs infect many types of mammals; the latter does not infect laboratory mice
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