J Bacteriol Virol.  2011 Dec;41(4):213-223. 10.4167/jbv.2011.41.4.213.

Herpesviral Interaction with Autophagy

• Liang C

• KMID: 2168649
• DOI: http://doi.org/10.4167/jbv.2011.41.4.213

Abstract

Autophagy constitutes a major catabolic hub for the quality control of intracellular entities of eukaryotic cells, and is emerging as an essential part of the host antiviral defense mechanism. However, in turn, viruses have evolved elegant strategies to co-opt various stages of the cellular autophagy pathway to establish virulence in vivo. This is particularly the case in the ubiquitous and persistent herpesvirus infection. In this review, I will focus on recent findings regarding the crosstalk between the herpes virus family and the autophagy pathway, with a look at the molecular mechanisms they use to disturb cells' autophagy regulation and eventually result in persistence and pathogenesis.

Keyword

Autophagy; Virus; Innate immunity; Infection

MeSH Terms

Autophagy
Eukaryotic Cells
Herpesviridae Infections
Humans
Immunity, Innate
Quality Control
Viruses

Figure

• 

  Figure 1. Overview of the autophagy pathway. Autophagy proceeds through a series of steps including autophagy signal induction, vesicle nucleation, membrane elongation, completion of the autophagosome, autophagosome maturation by fusion with endosomes and lysosomes, followed by degradation of autophagic cargoes, and recycling of the resulting molecules. The induction of autophagy by various stimuli signals through the ‘nutrient sensor’ mTOR. Under nutrient-rich conditions, mTOR binds and hyper-phosphorylates the ULK1/2 complex comprised of ULK1/2, Atg13, and FIP200 to repress autophagy. Inactivation of mTOR leads to the ULK1/2 complex hypophosphorylated, which allows the isolation membrane to expand. Vesicle nucleation is confined to the phosphatidylinositol-3-phosphate (PtdIns(3)P)-containing vesicles and is driven by the PI3KC3 complex, which consists of three major components, including Vps34, Vps15, and Beclin1. The activity of this lipid kinase complex is regulated by various positive and negative (black) regulators that associate with Beclin1. Two ubiquitin-like conjugation systems are involved in autophagosomal membrane expansion and completion: one is LC3-phosphatidylethanolamine (PE) conjugation and the other is Atg12-Atg5-Atg16 conjugation. The last steps of autophagy involve the docking and fusion of completed autophagosomes with endosomes and lysosomes sequentially, which signifies the maturation stage of autophagy regulated by various endosome/lysosome-related factors and inhibitory regulators (black). Finally, the inner membrane of the autophagosome and its sequestered materials are degraded by the lysosomal enzymes with the end products of proteolysis recycled. In antigen-presenting cells, autophagosome can also fuse with MHC class II loading compartments (MIICs), a subset of multivesicular bodies (MVBs), whereby autophagic cargoes including viral antigens can be delivered for MHC class II presentation.

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  Figure 2. Herpesviral interaction with the autophagy machinery. Autophagy can sanitize intracellular environment by directly capturing virions or viral components and delivering them for lysosomal degradation. It can also facilitate the antigen presentation of viral peptides to the MHC I/II pathway for adaptive immune response. The colored boxes present potential mechanisms that are used by herpesviruses to subvert or hijack cellular autophagy for their survival, propagation, and pathogenesis. The neurotropic α-herpesvirus HSV-1 proteins, ICP34.5, US11 and gB, have been shown to block the PKR-eIF2α-mediated autophagy activation or directly target Beclin1 for autophagy subversion (ICP34.5). The β-herpesvirus, HCMV, appears to blunt autophagy through both the mTOR-dependent or -independent pathways. γ-herpesviruses encode vBcl-2 and vFLIP to inhibit Beclin1-mediated autophagosome formation and Atg3-mediated autophagosome elongation, respectively, whereas the LMP1 protein of EBV and the RTA protein of KSHV were found to trigger autophagy either for the optimal survival of infected cells or for the acute replication and spreading of the virus. Thus, autophagy modulation is a common strategy employed by herpesviruses.

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