Varicella-zoster virus inhibits autophagosome-lysosome fusion and the degradation stage of mTOR-mediated autophagic flux

Graybill, Chiharu; Morgan, Michael J.; Levin, Myron J.; Damron, F. Heath

doi:10.1016/j.virol.2018.07.018

Cited by 19 publications

(18 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A similar mode of VZV entry by endocytosis rather than fusion has been demonstrated during VZV infection of CHO cells in the presence of 100 nM BAF (48). Finally, our data contradict several findings in a prior report about BAF effects on the VZV infectious cycle; the report did not include any electron microscopy of their BAF-treated VZV-infected cells (49).…”

Section: Discussioncontrasting

confidence: 76%

Progeny Varicella-Zoster Virus Capsids Exit the Nucleus but Never Undergo Secondary Envelopment during Autophagic Flux Inhibition by Bafilomycin A1

Girsch

Walters

Jackson

et al. 2019

J Virol

View full text Add to dashboard Cite

Varicella-zoster virus (VZV) is an alphaherpesvirus that lacks the herpesviral neurovirulence protein ICP34.5. The underlying hypothesis of this project was that inhibitors of autophagy reduce VZV infectivity. We selected the vacuolar proton ATPase inhibitor bafilomycin A1 for analysis because of its well-known antiautophagy property of impeding acidification during the late stage of autophagic flux. We documented that bafilomycin treatment from 48 to 72 h postinfection lowered VZV titers substantially (P ≤ 0.008). Because we were unable to define the site of the block in the infectious cycle by confocal microscopy, we turned to electron microscopy. Capsids were observed in the nucleus, in the perinuclear space, and in the cytoplasm adjacent to Golgi apparatus vesicles. Many of the capsids had an aberrant appearance, as has been observed previously in infections not treated with bafilomycin. In contrast to prior untreated infections, however, secondary envelopment of capsids was not seen in the trans-Golgi network, nor were prototypical enveloped particles with capsids (virions) seen in cytoplasmic vesicles after bafilomycin treatment. Instead, multiple particles with varying diameters without capsids (light particles) were seen in large virus assembly compartments near the disorganized Golgi apparatus. Bafilomycin treatment also led to increased numbers of multivesicular bodies in the cytoplasm, some of which contained remnants of the Golgi apparatus. In summary, we have defined a previously unrecognized property of bafilomycin whereby it disrupted the site of secondary envelopment of VZV capsids by altering the pH of the trans-Golgi network and thereby preventing the correct formation of virus assembly compartments. IMPORTANCE This study of VZV assembly in the presence of bafilomycin A1 emphasizes the importance of the Golgi apparatus/trans-Golgi network as a platform in the alphaherpesvirus life cycle. We have previously shown that VZV induces levels of autophagy far above the basal levels of autophagy in human skin, a major site of VZV assembly. The current study documented that bafilomycin treatment led to impaired assembly of VZV capsids after primary envelopment/de-envelopment but before secondary reenvelopment. This VZV study also complemented prior herpes simplex virus 1 and pseudorabies virus studies investigating two other inhibitors of endoplasmic reticulum (ER)/Golgi apparatus function: brefeldin A and monensin. Studies with porcine herpesvirus demonstrated that primary enveloped particles accumulated in the perinuclear space in the presence of brefeldin A, while studies with herpes simplex virus 1 documented an impaired secondary assembly of enveloped viral particles in the presence of monensin.

show abstract

Section: Discussioncontrasting

confidence: 76%

Progeny Varicella-Zoster Virus Capsids Exit the Nucleus but Never Undergo Secondary Envelopment during Autophagic Flux Inhibition by Bafilomycin A1

Girsch

Walters

Jackson

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

“…Because of the importance of autophagy data for our proposed studies, we decided to confirm prior observations about increased microtubule-associated protein 1 light-chain 3-II (MAP1 LC3-II or LC3-II) in Pompe cells. We also wanted to repeat our original data about increased LC3-II after VZV infection of MRC-5 cells as a positive control, because another laboratory had not found a similar response ( 21 ). When performing this experiment in MRC-5 cells, we allowed the cells to become confluent before infection ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Exocytosis of Progeny Infectious Varicella-Zoster Virus Particles via a Mannose-6-Phosphate Receptor Pathway without Xenophagy following Secondary Envelopment

Girsch

Jackson

Carpenter

et al. 2020

J Virol

View full text Add to dashboard Cite

The literature on egress of different herpesviruses after secondary envelopment is contradictory. In this report, we investigated varicella-zoster virus (VZV) egress in a cell line from a child with Pompe Disease, a glycogen storage disease caused by a defect in the enzyme required for glycogen digestion. In Pompe cells, both the late autophagy pathway and the mannose-6-phosphate receptor (M6PR) pathway are interrupted. We have postulated that intact autophagic flux was required for higher recoveries of VZV infectivity. To test that hypothesis, we infected Pompe cells and then assessed the VZV infectious cycle. We discovered that the infectious cycle in Pompe cells was remarkably different from either fibroblast or melanoma cells. No large late endosomes filled with VZV particles were observed in Pompe cells; only individual viral particles in small vacuoles were seen. The distribution of the M6PR pathway (trans Golgi network to late endosome) was constrained in infected Pompe cells. When analyzed with two different anti-M6PR antibodies, extensive co-localization of the major VZV glycoprotein gE (known to contain M6P residues) and the M6PR was documented in the viral highways at the surface of non-Pompe cells after maximum intensity projection of confocal z-stacks, but neither gE nor M6PR was seen in abundance at the surface of infected Pompe cells. Taken together, our results suggested that (i) Pompe cells lacked a VZV trafficking pathway within M6PR-positive large endosomes and (ii) most infectious VZV in conventional cell substrates was transported via large M6PR-positive vacuoles without degradative xenophagy to the plasma membrane. Importance. The long term goal of this research has been to determine why VZV, when grown in cultured cells, invariably is more cell associated with lower titer as compared with other alpha herpes viruses such as herpes simplex virus 1 (HSV1) or pseudorabies virus (PRV). Data from both HSV1 and PRV laboratories have identified a Rab6 secretory pathway for transport of single enveloped viral particles from the trans Golgi network within small vacuoles to the plasma membrane. In contrast, post-secondary envelopment in fibroblast or melanoma cells, multiple infectious VZV particles accumulated within large M6PR-positive late endosomes that were not degraded en route to the plama membrane. We propose that this M6PR pathway is most utilized in VZV infection, least utilized in HSV1 infection, with PRV being closer to HSV1. Supportive data from other VZV, PRV and HSV1 laboratories about evidence for two egress pathways are included in the Discussion.

show abstract

“…Thus, VZV partially inhibits the latestage of mTOR-mediated autophagic lux and the inhibitory effects are more pronounced when the cells are under stress [109]. Also, inhibition or block of autophagic lux may yield higher VZV titers [111].…”

Section: (3) Acquired Disordersmentioning

confidence: 99%

“…Autophagy is an ancient survival strategy and a well-recognized catabolic process by a stressed cell during which misfolded or damaged proteins are engulfed within double-walled cytoplasmic granules called autophagosomes [47,89,108,109]. The 3 major autophagy pathways that exist in mammals include: microautophagy, macroautophagy, and chaperone-mediated autophagy [107,110,111]. The molecular machinery of autophagy which generates autophagosomes in cells was originally described by Yoshinori Ohsumi who was awarded Nobel prize in physiology and medicine in 2016 [107].…”

Section: (3) Acquired Disordersmentioning

confidence: 99%

“…Autophagy is a highly conserved pathway among eukaryotes that involves recognition, capture, and traf icking of various intracellular components to the lysosome for degradation. So, it is responsible for maintaining cellular homeostasis in response to various internal and external stimuli [110,111]. Autophagy is tightly controlled by a set of autophagy-related gene proteins and secretory autophagy is a mechanism by which viruses replicate and spread [110].…”

Section: (3) Acquired Disordersmentioning

confidence: 99%

See 1 more Smart Citation

The beneficial effects of varicella zoster virus

Al-Anazi¹,

Wk²,

Al-Jasser³

2019

J Hematol Clin Res

View full text Add to dashboard Cite

Varicella zoster virus behaves differently from other herpes viruses as it differs from them in many aspects. Recently, there has been growing evidence on the benefi cial effects of the virus in immune compromised hosts and these effects are translated into prolongation of survival. The reported benefi cial effects of the virus include: (1) stimulation of bone marrow activity in patients with hematologic malignancies and bone marrow failure syndromes, (2) antitumor effects in various hematologic malignancies and solid tumors, and (3) association with graft versus host disease which has anticancer effects. Additionally, there are several reports on the safety of the live-attenuated even in severely immune suppressed individuals and on the emerging role of the virus in cancer immunotherapy. In this review, the following aspects of the virus will be thoroughly discussed: (1) new data on the genetic background, pathogenesis, vaccination, and new therapeutic modalities; (2) bone marrow microenvironment and hematopoiesis; (3) cells involved in the pathogenesis of the virus such as: mesenchymal stem cells, dendritic cells, natural killer cells, T-cells and mononuclear cells; (4) cellular proteins such as open reading frames, glycoproteins, promyelocytic leukemia protein, chaperons, and SUMOs; (5) extracellular vesicles, exosomes, and micro-RNAs; and (6) signaling pathways, cytokines, and interferons.

show abstract

Varicella-zoster virus inhibits autophagosome-lysosome fusion and the degradation stage of mTOR-mediated autophagic flux

Cited by 19 publications

References 35 publications

Progeny Varicella-Zoster Virus Capsids Exit the Nucleus but Never Undergo Secondary Envelopment during Autophagic Flux Inhibition by Bafilomycin A1

Progeny Varicella-Zoster Virus Capsids Exit the Nucleus but Never Undergo Secondary Envelopment during Autophagic Flux Inhibition by Bafilomycin A1

Exocytosis of Progeny Infectious Varicella-Zoster Virus Particles via a Mannose-6-Phosphate Receptor Pathway without Xenophagy following Secondary Envelopment

The beneficial effects of varicella zoster virus

Contact Info

Product

Resources

About