O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

Abstract

26Viruses hijack the host cell machinery to promote viral replication; however, the mechanism 27 by which metabolic reprogramming regulates innate antiviral immunity in the host remains 28 elusive. Herein, we found that Hepatitis B virus (HBV) infection upregulates glucose 29 transporter 1expression, promotes hexosamine biosynthesis pathway (HBP) activity, and 30 enhances O-linked β-N-acetylglucosamine (O-GlcNAc) modification of downstream proteins. 31 HBP-mediated O-GlcNAcylation positively regulates host antiviral response against HBV in 32 vitro and in vivo. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation 33 of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) on 34 Ser93 stabilizes SAMHD1 and enhances its antiviral activity. In addition, O-GlcNAcylation of 35 SAMHD1 promoted its antiviral activity against human immunodeficiency virus-1 in vitro. In 36 conclusion, the results of our study reveal a link between HBP, O-GlcNAc modification, and 37 innate antiviral immunity by targeting SAMHD1. Therefore, the results of this study 38 demonstrate a strategy for the potential treatment of HBV infection by modulating HBP 39 activity. 40 41 Keywords: Hepatitis B virus / O-linked β-N-acetylglucosamine modification / sterile alpha 42 motif and histidine/aspartic acid domain-containing protein 1 / antiviral immunity 43 /Hexosamine biosynthetic pathway 44 2 45Immunometabolism is an emerging field that highlights the importance of specific metabolic 46 pathways in immune regulation. Metabolic enzymes, such as glyceraldehyde 3-phosphate 47 dehydrogenase and pyruvate kinase isozyme M2 can directly modulate immune cell 48 activation (Chang et al, 2013; Palsson-McDermott et al, 2015). In addition to providing 49 energy and building blocks for biosynthesis, metabolites have been shown to participate in 50 epigenetic modification and signaling transduction. the glycolytic product lactate not only 51 regulates gene expression by histone acetylation (Zhang et al, 2019a), but also acts as a 52 suppressor of type I interferon signaling by interacting with the mitochondrial antiviral 53 signaling protein MAVS (Zhang et al, 2019b). Itaconate-another important metabolite for 54 immune function-downregulates type I interferon signaling during viral infection by 55 promoting alkylation of Kelch-like ECH-associated protein 1 and activation of 56 anti-inflammatory proteins, including nuclear factor erythroid 2-related factor 2 (Mills et al, 57 2018, 1; O'Neill & Artyomov, 2019).58 59 Viruses are obligate parasites that rely on the biosynthetic machinery of the host to complete 60 their life cycle. They hijack the host cell machinery upon entry to fulfill their energetic and 61 biosynthetic demands for viral replication. Human cytomegalovirus (HCMV) and herpes 62 simplex virus-1 (HSV-1) remodel host cells to perform distinct, virus-specific metabolic 63 programs (Vastag et al, 2011). HCMV reprograms host metabolism by upregulating the 64 expression of carbohydrate-response element bind...

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

“…ACE2 (virus-binding receptor) blockers, antimalarials; antivirals; immunoenhancers, monoclonal antibodies, and vaccines (Zhang et al, 2020) are proposed for COVID-19 treatment. In silico approaches (Mercurio et al, 2020) driven potential drug candidates (Balkrishna, 2020), non-human primate model for COVID-19 pathogenesis (Lu et al, 2020), and nutritional supplements (lactoferrin) (Chang et al, 2020), are other research guided strategies that are being actively investigated. However, exploring COVID-19 treatment still remains a global challenge (Mohta et al, 2020), and accelerating drug development through repurposed FDA approved drugs is encouraged for COVID-19 treatment, which involves employing pathogen-or hostdirected approaches that may potentiate anti-viral immune response by interfering with host cell factors or dampening pro-inflammatory cytokine storm (Gordy et Further, the emerging studies indicate that COVID-19 is commonly complicated with coagulopathy (Gris J-Christophe et al, 2020; Connors and Levy, 2020), marked by higher platelet count, and elevated D-dimer (Yin et al, 2020;.…”