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. 2012 Aug 27;1(3):617-30.
doi: 10.3390/cells1030617.

How human tumor viruses make use of autophagy

Zachary L Pratt  1 , Bill Sugden  2
Affiliations

How human tumor viruses make use of autophagy

Zachary L Pratt et al. Cells. .

Abstract

Viruses commandeer regulatory pathways of their hosts to optimize their success as cellular parasites. The human tumor viruses, Epstein-Barr Virus (EBV), Kaposi's Sarcoma Herpesvirus (KSHV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) all affect autophagy for their own ends. EBV and KSHV regulate it during latent infections, a phase when no progeny virus is produced, while HBV and HCV use autophagy to promote their productive infections. Here we shall compare and contrast how these human tumor viruses regulate autophagy and what they gain by the appropriation of this cellular pathway.

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Figures

Figure 1
Figure 1
Autophagy is initiated by stimuli that activate the phosphatidylinositol 3-phosphate kinase, Vps34. Vps34 generates phosphatidylinositol 3-phosphate, a substrate for the forming autophagosome, and its enzymatic activity is dependent on Beclin 1. For its localization in the phagophore, the unclosed double-membrane precursor to the autophagosome, the light chain 3 (LC3) is conjugated to phosphatidylethanolamine (PE) via an ubiquitin-like conjugation pathway. LC3 is cleaved from its inactive precursor form by ATG4B to render it cytosolic, and subsequently conjugated to PE via its binding the E2-like ligase, autophagy related 3 homolog (ATG3), and its transfer to the E3-like ATG16L complex (ATG16L, ATG5, and ATG12). Autophagy can be stimulated via the Unfolded Protein Response (UPR) via the phosphorylation and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). Active PERK phosphorylates the eukaryotic initiation factor 2 alpha (eIF2α). Phospho-eIF2α cannot translate capped mRNAs, but can translate mRNAs with internal ribosome entry sites (IRES), such as activated transcription factor 4 (ATF4). ATF4 activates the transcription of LC3 and Beclin 1 to induce autophagy. Human tumor viruses can regulate autophagy at several steps of the pathway. Both latent membrane protein 1 (LMP1) and the small surface protein of HBV (HBs) stimulate the UPR and induce autophagy. LMP1’s induction of autophagy regulates its degradation in autophagolysosomes. The Epstein-Barr nuclear antigen 1 (EBNA1) also can localize to autophagosomes and is degraded in autophagolysosomes, where epitopes of EBNA1 are generated for their presentation on MHC class II molecules. Autophagy fosters HBV’s productive infection. In addition to HBs, the Hepatitis B X protein (HBx) can stimulate autophagy via its interaction with Vps34. Autophagy can support HBV’s envelopment or reverse transcription. The non-structural proteins of HCV, NS4B and NS5B induce autophagy; the former appears to interact with Vps34, while the latter promotes LC3’s conjugation to PE by binding ATG5. Autophagy inhibits the cellular interferon response during the early stages of HCV’s infection. In contrast to NS5B, the KSHV viral FADD-like interleukin-1 beta-converting enzyme inhibitory protein (v-FLIP) inhibits LC3’s lipid-conjugation by competing with it for ATG3. v-FLIP inhibits autophagy-induced apoptosis and senescence of KSHV-positive cells. Autophagy is induced by replication and transactivator (RTA) to support KSHV’s replication, and v-FLIP may inhibit the productive life-cycle of the virus by repressing autophagy.
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