Cytomegaloviruses Exploit Recycling Rab Proteins in the Sequential Establishment of the Assembly Compartment.

Pero Lučin,Ljerka Kareluša,Stipan Jonjić,Gordana Blagojević Zagorac,Marina Marcelić,Hana Mahmutefendić Lučin,Berislav Lisnić,Silvija Lukanović Jurić,Natalia Jug Vučko,Valentino Pavišić

doi:10.3389/fcell.2018.00165

Pero Lučin, Ljerka Kareluša + Show 8 more

Open Access

https://doi.org/10.3389/fcell.2018.00165

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Abstract

Cytomegaloviruses (CMV) reorganize membranous system of the cell in order to develop a virion assembly compartment (VAC). The development starts in the early (E) phase of infection with the reorganization of the endosomal system and the Golgi and proceeds to the late phase until newly formed virions are assembled and released. The events in the E phase involve reorganization of the endosomal recycling compartment (ERC) in a series of cellular alterations that are mostly unknown. In this minireview, we discuss the effect of murine CMV infection on Rab proteins, master regulators of membrane trafficking pathways, which in the cascades with their GEFs and GAPs organize the flow of membranes through the ERC. Immunofluorescence analyzes of murine CMV infected cells suggest perturbations of Rab cascades that operate at the ERC. Analysis of cellular transcriptome in the course of both murine and human CMV infection demonstrates the alteration in expression of cellular genes whose products are known to build Rab cascades. These alterations, however, cannot explain perturbations of the ERC. Cellular proteome data available for human CMV infected cells suggests the potential role of RabGAP downregulation at the end of the E phase. However, the very early onset of the ERC alterations in the course of MCMV infection indicates that CMVs exploit Rab cascades to reorganize the ERC, which represents the earliest step in the sequential establishment of the cVAC.

Highlights

Cytomegaloviruses, like other herpesviruses, induce extensive reorganization of cellular functions, including the rearrangement of the membranous system (Johnson and Baines, 2011; Henaff et al, 2012)
It has been shown that Rab14 controls trafficking and recycling of clathrin-dependent endocytic (CDE) cargo at intermediates between early/sorting endosomes (EE/SEs) and the endosomal recycling compartment (ERC) (Linford et al, 2012), it appears that murine CMV (MCMV) infection does not affect these intermediates and that Rab14 is recruited to more peripheral endosomal compartments (Figure 1C), which mediates transport between EEs and the the trans-Golgi network (TGN) (Reed et al, 2013)
Analysis of the perinuclear aggregate in the E phase of MCMV infection indicates that CMV exploits multiple Rab proteins to reorganize the ERC into the core of the cytoplasmic virion assembly compartment (cVAC)

Summary

Introduction

Cytomegaloviruses, like other herpesviruses, induce extensive reorganization of cellular functions, including the rearrangement of the membranous system (Johnson and Baines, 2011; Henaff et al, 2012). In C. elegans epithelial cells Rab5 recruits an effector which promote interaction of Rab10 GEF with Rab10 (Liu et al, 2018), whereas Rab10 recruits GAP for Rab5 at the endosomes (Liu and Grant, 2015) thereby facilitating the exit of recycling cargo from SEs. accumulation of Rab10positive membranes in the perinuclear aggregate of MCMVinfected cells (Figure 1C) indicates expansion of Rab10-positive intermediates that mediate transport into the ERC and suggest altered recruitment of Rab10 GAP by a downstream cascade.

Results

Conclusion