HCMV Induced Alterations to Endocytic Sorting

Abstract

The maintenance of cell surface proteins is critical to the ability of a cell to sense and respond to information in its environment. As such, modulation of cell surface composition and receptor trafficking is a potentially important target of control in virus infection. Sorting endosomes (SEs) are control stations regulating the recycling or degradation of internalized plasma membrane proteins. Here we report that human cytomegalovirus (HCMV), a ubiquitous beta herpesvirus, alters the fate of internalized clathrin-independent endocytosis (CIE) cargo proteins, retaining them in virally reprogrammed SEs. We show that the small G protein ARF6, a regulator of CIE trafficking, is highly associated with SE membranes, relative to uninfected cells. This finding suggests that ARF6 and CIE cargo egress from the SE is diminished by infection. Over expression of the ubiquitin specific protease (USP) 6, also known as TRE17, was sufficient to restore ARF6 and some ARF6 cargo trafficking to the cell surface in infected cells. The USP-activity of TRE17 is required to rescue both ARF6 and associated cargo from SE retention in infection. Intriguingly, TRE17 expression does not affect all CIE cargos retained at SEs in infection. Although TRE17 mediates the trafficking of internalized major histocompatibility complex type I (MHCI) to the cell surface in uninfected cells, MHCI is insensitive to TRE17-mediated trafficking in the context of HCMV infection. These findings demonstrate a reprogramming of endocytic trafficking by HCMV infection and suggests that HCMV hijacks the normal sorting machinery and selectively sorts specific cargos into endocytic micro-domains that are subject to alternate sorting fates.