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.
Highlights
Varicella zoster virus (VZV) is a human herpesvirus [1]
Unrecognized when we first began our research into the glycobiology of VZV infection, infection, it has become apparent that VZV glycoprotein biosynthesis was associated with signs of it has become apparent that VZV glycoprotein biosynthesis was associated with signs of endoplasmic reticulum (ER) stress [17]
The alternatively spliced higher-molecular-weight form, XBP1(s), was readily visible at both 72 and 96 hpi, and first became detectable at 48 h hpi [7]. These results demonstrated unequivocally another distinctive sign of a VZV-induced ER stress response—that the inositol-requiring element 1 (IRE1) arm of the unfolded protein response (UPR) was upregulated in VZV-infected cells
Summary
Varicella zoster virus (VZV) is a human herpesvirus [1]. VZV is an alpha herpesvirus, as are herpes simplex virus (HSV) types 1 and 2. Over ~70 million years of evolution, the VZV genome lost all herpesvirus. Over ~70 years of evolution, VZV genome all genes not genes not essential its survival [3].million. CellsWeleads to both observed that infection in cultured cells leads to both increased endoplasmic reticulum (ER). VZV, unlike accommodated to autophagy without the need for any virally encoded inhibitors. Electron microscopy: Monolayer of VZV-infected cells at 96 h after infection. The viral particles (B) Electron microscopy: Monolayer of VZV-infected cells at 96 h after infection. The viral particles (arrows) are enclosed in cytoplasmic vesicles that traffic to and fuse with the outer cell membrane. Viral particles are not released from the outer cell membrane
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