Article

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

Columbia University, New York, New York, United States
Cell host & microbe (Impact Factor: 12.33). 04/2007; 1(1):23-35. DOI: 10.1016/j.chom.2006.12.001
Source: PubMed

ABSTRACT

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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    • "Functional autophagy is essential for cellular homeostasis, cell viability under stress conditions, and innate host defense mechanisms against viral and bacterial infections (Levine, 2005). A growing list of viruses, including Herpes simplex virus (HSV-1), human cytomegalovirus (HCMV) and Kaposi sarcoma-associated herpes virus (KSHV), express their own proteins to inhibit the formation of autophagosome (Chaumorcel et al. , 2012, Lee et al. , 2009, Orvedahl et al. , 2007), while human immunodeficiency virus (HIV) blocks the maturation stages of autophagy protecting HIV from degradation (Kyei et al. , 2009). However, viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) exploit autophagy for their replication (Dreux et al. , 2009, Sir et al. , 2010). "
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    • "However, it remains contro‐ versial [75, 76]. In HSV-1 (Herpes Simplex Virus), the virulence factor ICP34.5 inhibits autophagy via inhibition of Beclin 1 and PKR [77], and Us3 acts as a viral Akt surrogate to activate mTORC1 inhibiting host autophagy [78]. Curiously, additional members of the herpes virus family employ similar strategies to inhibit autophagy. "
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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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