bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2023–05–14
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. EBNA2 mediates lipid metabolism and tumorigenesis through activation of ATF4 pathway.
  2. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.
  3. SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.
  4. Viral subversion of selective autophagy is critical for biogenesis of virus replication organelles.
  5. Influenza Virus-Induced Paracrine Cellular Senescence of the Lung Contributes to Enhanced Viral Load.
  6. Voltage-dependent anion channels: Key players in viral infection.
  7. Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes.
  8. Antiviral activity of glucosylceramide synthase inhibitors in alphavirus infection of the central nervous system.
  9. Respiratory virus-specific nasopharyngeal lipidome signatures and severity in infants with bronchiolitis: A prospective multicenter study.
  10. The Host Protein CAD Regulates the Replication of FMDV through the Function of Pyrimidines' De Novo Synthesis.
  1. Am J Cancer Res. 2023 ;13(4): 1363-1376
    EBNA2 mediates lipid metabolism and tumorigenesis through activation of ATF4 pathway.
    Jia Feng, Ping Zhang, Paul Yao, Hongyu Zhang.
      Epstein-Barr virus (EBV) can infect the majority of the human population with no obvious symptoms and is associated with tumor development, although the mechanism is still largely unknown. In this study, we investigated the role and the underlying mechanism of EBV nuclear antigen 2 (EBNA2) in tumorigenesis. We found that the infection of EBNA2 in human B lymphocytes (HBL) upregulated the expression of activating transcription factor 4 (ATF4). Furthermore, we used gene expression or knockdown approach to demonstrate the effect of EBNA2 on redox balance, mitochondrial function, lipid metabolism, and cell proliferation in both HBL and EBV-transformed lymphocyte cell line (LCL). More importantly, we applied in vivo xenograft tumor mouse model to explore the contribution of EBNA2 and ATF4 in tumor growth and mouse survival. Mechanistically, we revealed that EBNA2 exposure caused persistent expression of ATF4 via EBNA2-mediated epigenetic changes, which increased the binding ability of upstream stimulating factor 1 (USF1) on the ATF4 promoter. ATF4 activation in HBL cells modulated the expression of lipid metabolism-related genes and potentiated fatty acid oxidation and lipogenesis. Conversely, knockdown of either EBNA2 or ATF4 in LCL suppressed lipid metabolism, modulated redox balance and mitochondrial function, as well as inhibited tumor cell proliferation. In consistent with these findings from in vitro study, an in vivo xenograft model confirmed that knockdown of either EBNA2 or ATF4 inhibited the gene expression of SREBP1, ChREBP, and FAS, as well as suppressed tumor growth and prolonged animal survival. Collectively, this study demonstrates that EBNA2 mediates tumorigenesis through ATF4 activation and the modulation of lipid metabolism; therefore, our findings provide a novel avenue for the clinical treatment of EBV-mediated cancer.
    Keywords:  ATF4 and USF1; EBNA2; EBV; lipid metabolism
  2. Cell Commun Signal. 2023 May 08. 21(1): 102
    Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.
    Dong Lin, Yijia Chen, Ali Riza Koksal, Srikanta Dash, Yucel Aydin.
       BACKGROUND: Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed.
    METHODS: Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection.
    RESULTS: Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection.
    CONCLUSION: Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.
    Keywords:  Chronic hepatitis C virus (HCV) infection; Direct-acting antiviral agents (DAA); Endoplasmic reticulum stress (ER stress); Glycogen synthase kinase-3β (GSK-3β); Hepatocellular carcinoma (HCC); Protein kinase A (PKA); Wnt/β-catenin
    DOI:  https://doi.org/10.1186/s12964-023-01081-9
  3. bioRxiv. 2023 Apr 24. pii: 2023.04.22.537917. [Epub ahead of print]
    SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.
    Jonathan P Davies, Athira Sivadas, Katherine R Keller, Richard J H Wojcikiewicz, Lars Plate.
      Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis pathways during infection through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR). The UPR regulates protein translation, increases protein folding capacity and enhances endoplasmic reticulum (ER) biogenesis to alleviate ER stress caused by accumulation of misfolded proteins. CoVs depend on host machinery to generate large amounts of viral protein and manipulate ER-derived membranes to form double-membrane vesicles (DMVs), which serve as replication sites, making the UPR a key host pathway for CoVs to hijack. Despite the importance of CoV nonstructural proteins (nsps) in mediating replication, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, which is a key driver of DMV formation, on the UPR using quantitative proteomics. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological activation of the ATF6 pathway. To determine how nsp3.1 and nsp4 might tune the UPR in concert, both proteins were co-expressed demonstrating that nsp3.1 does not suppress nsp4-mediated ATF6 activation but does suppress PERK activation. A meta-analysis of SARS-CoV-2 infection proteomics data reveals a time-dependent activation of PERK protein markers early in infection, which subsequently fades. This temporal regulation suggests a role for nsps tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic PERK activation. This work furthers our understanding of CoV-host proteostasis interactions and identifies potential areas to target for anti-viral therapies.
    DOI:  https://doi.org/10.1101/2023.04.22.537917
  4. Nat Commun. 2023 May 10. 14(1): 2698
    Viral subversion of selective autophagy is critical for biogenesis of virus replication organelles.
    Yun Lan, Sophie Wilhelmina van Leur, Julia Ayano Fernando, Ho Him Wong, Martin Kampmann, Lewis Siu, Jingshu Zhang, Mingyuan Li, John M Nicholls, Sumana Sanyal.
      Infection by many (+)RNA viruses is accompanied by ER-expansion and membrane remodelling to form viral replication organelles, followed by assembly and secretion of viral progenies. We previously identified that virus-triggered lipophagy was critical for flaviviral assembly, and is driven by the lipid droplet associated protein Ancient ubiquitin protein 1 (Aup1). A ubiquitin conjugating protein Ube2g2 that functions as a co-factor for Aup1 was identified as a host dependency factor in our study. Here we characterized its function: Ube2g2-deficient cells displayed a dramatic reduction in virus production, which could be rescued by reconstituting the wild-type but not the catalytically deficient (C89K) mutant of Ube2g2, suggesting that its enzymatic activity is necessary. Ube2g2 deficiency did not affect entry of virus particles but resulted in a profound loss in formation of replication organelles, and production of infectious progenies. This phenomenon resulted from its dual activity in (i) triggering lipophagy in conjunction with Aup1, and (ii) degradation of ER chaperones such as Herpud1, SEL1L, Hrd1, along with Sec62 to restrict ER-phagy upon Xbp1-IRE1 triggered ER expansion. Our results therefore underscore an exquisite fine-tuning of selective autophagy by flaviviruses that drive host membrane reorganization during infection to enable biogenesis of viral replication organelles.
    DOI:  https://doi.org/10.1038/s41467-023-38377-w
  5. Aging Dis. 2023 03 31.
    Influenza Virus-Induced Paracrine Cellular Senescence of the Lung Contributes to Enhanced Viral Load.
    Luise Schulz, Franziska Hornung, Antje Häder, Lukáš Radosa, Axel A Brakhage, Bettina Löffler, Stefanie Deinhardt-Emmer.
      Aging is a major risk factor associated with increased morbidity and mortality rates observed during respiratory infections. In this study, we investigated the role of influenza virus infections in the establishment of premature cellular senescence and paracrine macrophage-activated inflammation. We observed in our murine model a premature aging by the appearance of senescent cells in the lungs after 21 d of influenza A virus infection. By using murine ex vivo lung models, the influence of TNF-α on the establishment of cellular senescence was detectable. Our findings were proven by using conditioned media of infected human monocyte-derived macrophages on primary lung fibroblasts. Here, a distinct expression of senescence-associated parameters could be confirmed. Furthermore, senescent cells in the lungs strongly influenced subsequent viral infections. Our data demonstrated a higher viral load in senescent primary lung fibroblasts, indicating an intracellular effect on viral replication. Transcriptomic data revealed an increased regulation of JAK/STAT signaling in senescent IAV-infected cells accompanied with increased TRAIL expression. Additionally, senescent cells indicating low pH values, accelerating viral replication. Our study provides new insights into pathomechanisms of virus-induced cellular senescence. Hence, IAV infection induces premature senescence and subsequent infections in senescent cells lead to an increased viral replication.
    DOI:  https://doi.org/10.14336/AD.2023.0310
  6. Rev Med Virol. 2023 May 11. e2453
    Voltage-dependent anion channels: Key players in viral infection.
    Ahmed H Saadawy, Aya M Khalil, Lydia R Sidarous, Mostafa S Ibrahim, Tamer Z Salem.
      Viruses control the host cell by exploiting its molecular machinery to facilitate viral replication and propagation. Understanding different viral mechanisms and biochemical pathways is crucial for finding promising therapeutic solutions to viral infections. The mitochondrion is a vital organelle targeted by various types of viruses. More specifically, viruses interact with the voltage-dependent anion channel (VDAC), a porin protein found in the outer mitochondrial membrane. VDAC controls metabolite flux, regulates reactive oxygen species production, and promotes mitochondrial-mediated apoptosis by releasing pro-apoptotic proteins. Hence, a common pathogenic strategy used by many viruses seems to exploit natural pathways that VDAC regulates. This review aims to address the inhibition and enhancement roles of VDAC in viral pathogenesis and outlines multiple links and interactions between VDAC and viral proteins as potential antiviral targets.
    Keywords:  apoptosis; innate immunity; mitochondria; viral infection; virus inhibition; voltage-dependent anion channels
    DOI:  https://doi.org/10.1002/rmv.2453
  7. Med Oncol. 2023 May 11. 40(6): 174
    Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes.
    Rhuthuparna Malayil, Yogita Chhichholiya, Kanika Vasudeva, Harsh Vikram Singh, Tashvinder Singh, Sandeep Singh, Anjana Munshi.
      Oncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known drugs.
    Keywords:  BC; Metabolic reprogramming; Mitochondria; Signaling
    DOI:  https://doi.org/10.1007/s12032-023-02037-2
  8. Brain Commun. 2023 ;5(3): fcad086
    Antiviral activity of glucosylceramide synthase inhibitors in alphavirus infection of the central nervous system.
    Roy Avraham, Sharon Melamed, Hagit Achdout, Noam Erez, Ofir Israeli, Moria Barlev-Gross, Metsada Pasmanik-Chor, Nir Paran, Tomer Israely, Einat B Vitner.
      Virus-induced CNS diseases impose a considerable human health burden worldwide. For many viral CNS infections, neither antiviral drugs nor vaccines are available. In this study, we examined whether the synthesis of glycosphingolipids, major membrane lipid constituents, could be used to establish an antiviral therapeutic target. We found that neuroinvasive Sindbis virus altered the sphingolipid levels early after infection in vitro and increased the levels of gangliosides GA1 and GM1 in the sera of infected mice. The alteration in the sphingolipid levels appears to play a role in neuroinvasive Sindbis virus replication, as treating infected cells with UDP-glucose ceramide glucosyltransferase (UGCG) inhibitors reduced the replication rate. Moreover, the UGCG inhibitor GZ-161 increased the survival rates of Sindbis-infected mice, most likely by reducing the detrimental immune response activated by sphingolipids in the brains of Sindbis virus-infected mice. These findings suggest a role for glycosphingolipids in the host immune response against neuroinvasive Sindbis virus and suggest that UGCG inhibitors should be further examined as antiviral therapeutics for viral infections of the CNS.
    Keywords:  alphaviruses; antiviral drug; encephalitis; glucosylceramide; sphingolipids
    DOI:  https://doi.org/10.1093/braincomms/fcad086
  9. J Infect Dis. 2023 May 11. pii: jiad156. [Epub ahead of print]
    Respiratory virus-specific nasopharyngeal lipidome signatures and severity in infants with bronchiolitis: A prospective multicenter study.
    Michihito Kyo, Zhaozhong Zhu, Ryohei Shibata, Michimasa Fujiogi, Jonathan M Mansbach, Carlos A Camargo, Kohei Hasegawa.
       BACKGROUND: In infant bronchiolitis, recent evidence indicates that respiratory viruses (e.g., respiratory syncytial virus [RSV], rhinovirus [RV]) contribute to the heterogeneity of disease severity. Of the potential pathobiological molecules, lipids serve as signaling molecules in airway inflammation. However, little is known about the role of the airway lipidome in between-virus heterogeneity and disease severity.
    METHODS: In this multicenter prospective study of 800 infants hospitalized for RSV or RV bronchiolitis, we analyzed the nasopharyngeal lipidome data. We examined discriminatory lipids between RSV and RV infection and the association of the discriminatory lipids with bronchiolitis severity-defined by positive pressure ventilation (PPV) use.
    RESULTS: We identified 30 discriminatory nasopharyngeal lipid species and 8 fatty acids between RSV and RV infection. In the multivariable models adjusting for patient-level confounders, 8 lipid species-e.g., phosphatidylcholine (18:2/18:2) (adjOR 0.23, 95%CI 0.11-0.44, FDR=0.0004) and dihydroceramide (16:0) (adjOR 2.17, 95%CI 1.12-3.96, FDR=0.04)-were significantly associated with the risk of PPV use. Additionally, 6 fatty acids-e.g., eicosapentaenoic acid (adjOR 0.27, 95%CI 0.11-0.57, FDR=0.01)-were also significantly associated with the risk of PPV use.
    CONCLUSIONS: In infants hospitalized for bronchiolitis, the nasopharyngeal lipidome plays an important role in the pathophysiology of between-virus heterogeneity and disease severity.
    Keywords:  bronchiolitis; ceramide; eicosapentaenoic acid; glycerophospholipid metabolism; heterogeneity; lipids; mRNA; phosphatidylcholine; severity; sphingolipid metabolism
    DOI:  https://doi.org/10.1093/infdis/jiad156
  10. J Virol. 2023 May 10. e0036923
    The Host Protein CAD Regulates the Replication of FMDV through the Function of Pyrimidines' De Novo Synthesis.
    Pu Yang, Yuncong Yuan, Yidan Sun, Bonan Lv, Hang Du, Zhou Zhou, Zhuang Yang, Xuemei Liu, Huimin Duan, Chao Shen.
      Foot-and-mouth disease virus (FMDV) is a single-stranded picornavirus that causes economically devastating disease in even-hooved animals. There has been little research on the function of host cells during FMDV infection. We aimed to shed light on key host factors associated with FMDV replication during acute infection. We found that HDAC1 overexpression in host cells induced upregulation of FMDV RNA and protein levels. Activation of the AKT-mammalian target of rapamycin (mTOR) signaling pathway using bpV(HOpic) or SC79 also promoted FMDV replication. Furthermore, short hairpin RNA (shRNA)-induced suppression of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), a transcription factor downstream of the AKT-mTOR signaling pathway, resulted in downregulation of FMDV RNA and protein levels. Coimmunoprecipitation assays showed that the ACTase domain of CAD could interact with the FMDV 2C protein, suggesting that the ACTase domain of CAD may be critical in FMDV replication. CAD proteins participate in de novo pyrimidine synthesis. Inhibition of FMDV replication by deletion of the ACTase domain of CAD in host cells could be reversed by supplementation with uracil. These results revealed that the contribution of the CAD ACTase domain to FMDV replication is dependent on de novo pyrimidine synthesis. Our research shows that HDAC1 promotes FMDV replication by regulating de novo pyrimidine synthesis from CAD via the AKT-mTOR signaling pathway. IMPORTANCE Foot-and-mouth disease virus is an animal virus of the Picornaviridae family that seriously harms the development of animal husbandry and foreign trade of related products, and there is still a lack of effective means to control its harm. Replication complexes would generate during FMDV replication to ensure efficient replication cycles. 2C is a common viral protein in the replication complex of Picornaviridae virus, which is thought to be an essential component of membrane rearrangement and viral replication complex formation. The host protein CAD is a key protein in the pyrimidines de novo synthesis. In our research, the interaction of CAD and FMDV 2C was demonstrated in FMDV-infected BHK-21 cells, and it colocalized with 2C in the replication complex. The inhibition of the expression of FMDV 3D protein through interference with CAD and supplementation with exogenous pyrimidines reversed this inhibition, suggesting that FMDV might recruit CAD through the 2C protein to ensure pyrimidine supply during replication. In addition, we also found that FMDV infection decreased the expression of the host protein HDAC1 and ultimately inhibited CAD activity through the AKT-mTOR signaling pathway. These results revealed a unique means of counteracting the virus in BHK-21 cells lacking the interferon (IFN) signaling pathway. In conclusion, our study provides some potential targets for the development of drugs against FMDV.
    Keywords:  AKT-mTOR signaling pathway; CAD; FMDV; HDAC1; pyrimidines
    DOI:  https://doi.org/10.1128/jvi.00369-23
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