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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
Pathogens 2016, 5(4), 67; https://doi.org/10.3390/pathogens5040067
Received: 19 October 2016 / Revised: 22 November 2016 / Accepted: 2 December 2016 / Published: 10 December 2016
(This article belongs to the Special Issue Herpesviruses)
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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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. https://doi.org/10.3390/pathogens5040067

AMA Style

Grose C, Buckingham EM, Carpenter JE, Kunkel JP. Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking. Pathogens. 2016; 5(4):67. https://doi.org/10.3390/pathogens5040067

Chicago/Turabian Style

Grose, Charles; Buckingham, Erin M.; Carpenter, John E.; Kunkel, Jeremy P. 2016. "Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking" Pathogens 5, no. 4: 67. https://doi.org/10.3390/pathogens5040067

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