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.