Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction

Hua Lu, Natalia A. Cherepanova, Reid Gilmore, Joseph N. Contessa, Mark A Lehrman

Research output: Contribution to journalArticle

Abstract

Herpes simplex virus 1 (HSV-1) is a contagious neurotropic herpesvirus responsible for oral lesions and herpesviral encephalitis. The HSV-1 envelope contains N-glycosylated proteins involved in infection and that are candidate drug targets. NGI-1 is a small-molecule inhibitor of oligosaccharyltransferase (OST) complexes STT3A-OST and STT3B-OST, which catalyze cotranslational and post-translational N-glycosylation, respectively. Because host OSTs attach HSV-1 glycans, NGI-1 might have anti-HSV-1 activity. We evaluated HSV-1 function using NGI-1 and human embryonic kidney 293 knockout lines for OST isoform-specific catalytic and accessory subunits. N-glycosylation of 2 representative envelope proteins (gC and gD) was primarily dependent upon STT3A-OST, but to a large extent replaceable by STT3B-OST. Knockouts impairing STT3A- or STT3B-OST activity, by themselves, did not appreciably affect HSV-1 function (plaque-forming units, normalized to viral particles measured by unglycosylated capsid protein VP5 content). However, with cells lacking STT3B-OST activity (missing the catalytic subunit STT3B or the oxidoreductase subunits magnesium transporter 1/tumor suppressor candidate 3) and thus solely dependent upon STT3A-OST for N-glycosylation, NGI-1 treatment resulted in HSV-1 having cell type-dependent dysfunction (affecting infectivity with Vero cells much more than with the 293 lines). Ablation of post-translational N-glycosylation can therefore make HSV-1 infectivity, and possibly masking of immunogenic peptide epitopes by glycans, highly sensitive to pharmacological inhibition of cotranslational N-glycosylation.-Lu, H., Cherepanova, N. A., Gilmore, R., Contessa, J. N., Lehrman, M. A. Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction.

Original languageEnglish (US)
Pages (from-to)6801-6812
Number of pages12
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Human Herpesvirus 1
Viruses
Glycosylation
Polysaccharides
Catalytic Domain
dolichyl-diphosphooligosaccharide - protein glycotransferase
Vero Cells
Herpesviridae
Accessories
Capsid Proteins
Encephalitis
Ablation
Virion
Magnesium
Tumors
Epitopes
Oxidoreductases
Protein Isoforms
Proteins
Pharmacology

Keywords

  • glycobiology
  • glycoprotein
  • glycosylation
  • herpesvirus
  • lipid-linked oligosaccharide

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction. / Lu, Hua; Cherepanova, Natalia A.; Gilmore, Reid; Contessa, Joseph N.; Lehrman, Mark A.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 6, 01.06.2019, p. 6801-6812.

Research output: Contribution to journalArticle

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AB - Herpes simplex virus 1 (HSV-1) is a contagious neurotropic herpesvirus responsible for oral lesions and herpesviral encephalitis. The HSV-1 envelope contains N-glycosylated proteins involved in infection and that are candidate drug targets. NGI-1 is a small-molecule inhibitor of oligosaccharyltransferase (OST) complexes STT3A-OST and STT3B-OST, which catalyze cotranslational and post-translational N-glycosylation, respectively. Because host OSTs attach HSV-1 glycans, NGI-1 might have anti-HSV-1 activity. We evaluated HSV-1 function using NGI-1 and human embryonic kidney 293 knockout lines for OST isoform-specific catalytic and accessory subunits. N-glycosylation of 2 representative envelope proteins (gC and gD) was primarily dependent upon STT3A-OST, but to a large extent replaceable by STT3B-OST. Knockouts impairing STT3A- or STT3B-OST activity, by themselves, did not appreciably affect HSV-1 function (plaque-forming units, normalized to viral particles measured by unglycosylated capsid protein VP5 content). However, with cells lacking STT3B-OST activity (missing the catalytic subunit STT3B or the oxidoreductase subunits magnesium transporter 1/tumor suppressor candidate 3) and thus solely dependent upon STT3A-OST for N-glycosylation, NGI-1 treatment resulted in HSV-1 having cell type-dependent dysfunction (affecting infectivity with Vero cells much more than with the 293 lines). Ablation of post-translational N-glycosylation can therefore make HSV-1 infectivity, and possibly masking of immunogenic peptide epitopes by glycans, highly sensitive to pharmacological inhibition of cotranslational N-glycosylation.-Lu, H., Cherepanova, N. A., Gilmore, R., Contessa, J. N., Lehrman, M. A. Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction.

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