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


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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Available from: David A Leib
    • "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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    ABSTRACT: Influenza A virus (IAV) infection triggers autophagosome formation, but inhibits the fusion of autophagosomes with lysosomes. However, the role of autophagy in IAV replication is still largely unclarified. In this study, we aim to reveal the role of autophagy in IAV replication and the molecular mechanisms underlying the regulation. By using autophagy-deficient (Atg7-/-) MEFs, we demonstrated that autophagy deficiency significantly reduced the levels of viral proteins, mRNA and genomic RNAs (vRNAs) without affecting viral entry. We further found that autophagy deficiency lead to a transient increase in phosphorylation of mTOR and its downstream targets including 4E-BP1 and S6 at a very early stage of IAV infection, and markedly suppressed p70S6K phosphorylation at the late stage of IAV infection. Furthermore, autophagy deficiency resulted in impairment of Hsp90 induction in response to IAV infection. These results indicate that IAV regulates autophagy to benefit the accumulation of viral elements (synthesis of viral proteins and genomic RNA) during IAV replication. This regulation is associated with modulation of Hsp90 induction and mTOR/p70S6K signaling pathway. Our results provide important evidence for the role of autophagy in IAV replication and the mechanisms underlying the regulation.
    No preview · Article · Jan 2016 · The international journal of biochemistry & cell biology
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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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    ABSTRACT: Dengue virus (DENV) is one of the most prevalent human pathogens worldwide. It caus‐ es a huge socioeconomic burden with approximately 400 million infections per year, but yet there is no vaccine or antiviral that is currently effective against the disease. DENV is spread by the mosquitoes Aedes aegypti and Aedes albopictus, and viral replication within the mosquito vector is required for transmission to human host. During its replication cy‐ cle, the virus cause significant changes to the host transcriptome profile, especially in the metabolic and trafficking pathways. Recent studies have shown a strong association be‐ tween autophagy and lipid metabolism modulation. For many years, biochemistry studies have been forgotten and replaced by the most ad‐ vanced techniques and theories in molecular biology and their promises for solving the "life code"; however, after many years of strong molecular biology research, it had not found the key of many problems with which we have the elemental biosystems like vi‐ ruses. Decades of molecular virology investigations did not give more light about several cellular processes that occurred into the host cells when the infections happen. The mo‐ lecular virologists have cloned many viral genes, manipulating full viral genomes, and engineering chimeric constructs to study many details at the molecular level, but the host cell and the encrypted viruses do not want to reveal their secrets. Only with the new perspective of complex diseases, a new approach has emerged: An in‐ tegrative methodology wherein molecular cell biology is converging with the most pure and elegant biochemistry. In this way, more extensive research is necessary for future comparative analyses of the host and vector metabolic/signaling environments required for viral replication.
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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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    ABSTRACT: Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.
    Full-text · Article · Oct 2015 · Cell Reports
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