HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell host & microbe (Impact Factor: 12.33). 04/2007; 1(1):23-35. DOI: 10.1016/j.chom.2006.12.001
Source: PubMed


Autophagy is postulated to play a role in antiviral innate immunity. However, it is unknown whether viral evasion of autophagy is important in disease pathogenesis. Here we show that the herpes simplex virus type 1 (HSV-1)-encoded neurovirulence protein ICP34.5 binds to the mammalian autophagy protein Beclin 1 and inhibits its autophagy function. A mutant HSV-1 virus lacking the Beclin 1-binding domain of ICP34.5 fails to inhibit autophagy in neurons and demonstrates impaired ability to cause lethal encephalitis in mice. The neurovirulence of this Beclin 1-binding mutant virus is restored in pkr(-/-) mice. Thus, ICP34.5-mediated antagonism of the autophagy function of Beclin 1 is essential for viral neurovirulence, and the antiviral signaling molecule PKR lies genetically upstream of Beclin 1 in host defense against HSV-1. Our findings suggest that autophagy inhibition is a novel molecular mechanism by which viruses evade innate immunity and cause fatal disease.

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Article: HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein

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    • "To assess whether Akt antagonizes cGAS-mediated IFN response upon infection with DNA viruses, L929 cGAS À/À cells complemented with vector, mouse cGAS WT, or cGAS S291A were infected with mock or F strain HSV-1 WT or HSV-1 DICP34.5 mutant or the modified vaccina Ankara (MVA), followed by the measurement of IFN-b mRNA production. HSV-1 DICP34.5 mutant strain was included as a control since the GADD34 homology-containing ICP34.5 effectively counteracts the type I IFN response by binding four cellular proteins, Be- clin-1, TBK1, protein phosphatase 1a (PP1a), and eukaryotic translation initiation factor 2a (eIF2a) (Kanai et al., 2012; Li et al., 2011; Orvedahl et al., 2007). As previously shown (Liang et al., 2014), expression of cGAS WT induced much higher amounts of IFN-b mRNA upon HSV-1 DICP34.5 infection than upon HSV-1 infection. "
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    • "Subsequent work extended the idea of Beclin 1 as a main regulator of an anti-viral response. Several viruses encode a Beclin 1-binding protein, such as a Herpes Simplex Virus 1 protein, ICP34.5, and viruses lacking this domain are less pathogenic in a mouse encephalitis model (Orvedahl et al., 2007). ICP34.5 binding to Beclin 1 inhibits the formation of autophagosomes in neurons, suggesting that the virus has evolved to actively inhibit autophagy. "
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    • "Emerging evidence has suggested roles for autophagy in immunological responses including antimicrobial activity, antigen presentation, cytokine production, and regulation of lymphocytes [50,54]. For example, disruption of the virulence factor from the HSV-1 virus, which inhibited the host autophagy proteins, could prevent fatal encephalitis [55]. In addition, autophagy exhibited protective functions in the spleen, bone marrow, or liver through activation of immune responses such as detoxification and degradation of toxins and inflammatory proteins [56-58]. "
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