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Pathogens 2016, 5(4), 67; doi:10.3390/pathogens5040067

Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking

1
Virology Laboratory, Children’s Hospital, University of Iowa, Iowa City, IA 52242, USA
2
JC Wilt Infectious Diseases Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3L5, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Angus Wilson
Received: 19 October 2016 / Revised: 22 November 2016 / Accepted: 2 December 2016 / Published: 10 December 2016
(This article belongs to the Special Issue Herpesviruses)
View Full-Text   |   Download PDF [5834 KB, uploaded 10 December 2016]   |  

Abstract

Varicella-zoster virus (VZV) induces abundant autophagy. Of the nine human herpesviruses, the VZV genome is the smallest (~124 kbp), lacking any known inhibitors of autophagy, such as the herpes simplex virus ICP34.5 neurovirulence gene. Therefore, this review assesses the evidence for VZV-induced cellular stress, endoplasmic-reticulum-associated degradation (ERAD), and autophagic flux during the VZV infectious cycle. Even though VZV is difficult to propagate in cell culture, the biosynthesis of the both N- and O-linked viral glycoproteins was found to be abundant. In turn, this biosynthesis provided evidence of endoplasmic reticulum (ER) stress, including a greatly enlarged ER and a greatly diminished production of cellular glycoproteins. Other signs of ER stress following VZV infection included detection of the alternatively spliced higher-molecular-weight form of XBP1 as well as CHOP. VZV infection in cultured cells leads to abundant autophagosome production, as was visualized by the detection of the microtubule-associated protein 1 light chain 3-II (LC3-II). The degree of autophagy induced by VZV infection is comparable to that induced in uninfected cells by serum starvation. The inhibition of autophagic flux by chemicals such as 3-methyladenine or ATG5 siRNA, followed by diminished virus spread and titers, has been observed. Since the latter observation pointed to the virus assembly/trafficking compartments, we purified VZ virions by ultracentrifugation and examined the virion fraction for components of the autophagy pathway. We detected LC3-II protein (an autophagy marker) as well as Rab11 protein, a component of the endosomal pathway. We also observed that the virion-containing vesicles were single-walled; thus, they are not autophagosomes. These results suggested that some VZ virions after secondary envelopment were transported to the outer cell membrane in a vesicle derived from both the autophagy and endosomal pathways, such as an amphisome. Thus, these results demonstrate that herpesvirus trafficking pathways can converge with the autophagy pathway. View Full-Text
Keywords: autophagy; varicella-zoster virus; cytomegalovirus; herpes simplex virus; glycoproteins; unfolded protein response; ER-associated degradation; XBP1; xenophagy autophagy; varicella-zoster virus; cytomegalovirus; herpes simplex virus; glycoproteins; unfolded protein response; ER-associated degradation; XBP1; xenophagy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Grose, C.; Buckingham, E.M.; Carpenter, J.E.; Kunkel, J.P. Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking. Pathogens 2016, 5, 67.

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