O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development

Webster, Danielle M.; Teo, Chin Fen; Sun, Yuhua; Włoga, Dorota; Gay, Steven; Klonowski, Kimberly D.; Wells, Lance; Dougan, Scott T.

doi:10.1186/1471-213x-9-28

Cited by 98 publications

(94 citation statements)

References 87 publications

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“…O-GlcNAcylation by OGT is one of the most abundant posttranslational modifications in mammalian cells, with more than 30% of the human proteome consisting of OGlcNAcylated proteins (30). This modification is essential for development and proper cell function, and deletion of the OGT gene in vertebrates leads to developmental defects and embryonic lethality (31,32). OGT is highly conserved in higher eukaryotes and is abundantly expressed in all tissues in the body (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

Angelova

Ortiz‐Meoz

Walker

et al. 2015

J Virol

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O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies nuclear and cytoplasmic proteins via O-linked addition of a single N-acetylglucosamine (GlcNAc) moiety. Among the many targets of OGT is host cell factor 1 (HCF-1), a transcriptional regulator that is required for transactivation of the immediate-early genes of herpes simplex virus (HSV). HCF-1 is synthesized as a large precursor that is proteolytically cleaved by OGT, which may regulate its biological function. In this study, we tested whether inhibition of the enzymatic activity of OGT with a small molecule inhibitor, OSMI-1, affects initiation of HSV immediate-early gene expression and viral replication. We found that inhibiting OGT's enzymatic activity significantly decreased HSV replication. The major effect of the inhibitor occurred late in the viral replication cycle, when it reduced the levels of late proteins and inhibited capsid formation. However, depleting OGT levels with small interfering RNA (siRNA) reduced the expression of HSV immediate-early genes, in addition to reducing viral yields. In this study, we identified OGT as a novel cellular factor involved in HSV replication. Our results obtained using a small molecule inhibitor and siRNA depletion suggest that OGT's glycosylation and scaffolding functions play distinct roles in the replication cycle of HSV. IMPORTANCE Antiviral agents can target viral or host gene products essential for viral replication. O-GlcNAc transferase (OGT)is an important cellular enzyme that catalyzes the posttranslational addition of GlcNAc sugar residues to hundreds of nuclear and cytoplasmic proteins, and this modification regulates their activity and function. Some of the known OGT targets are cellular proteins that are critical for the expression of herpes simplex virus (HSV) genes, suggesting a role for OGT in the replication cycle of HSV. In this study, we found that OGT is required for efficient expression of viral genes and for assembly of new virions. Thus, we identify OGT as a novel host factor involved in the replication of HSV and a potential target for antiviral therapy. Herpes simplex virus (HSV) causes a variety of infections that can lead to considerable morbidity and mortality in immunocompromised patients and neonates (1). Lytic replication of HSV occurs in a highly regulated fashion with sequential expression of immediate-early (IE), early (E), and late (L) viral genes (1). IE gene transcription occurs in the absence of de novo viral protein synthesis and requires the viral VP16 tegument protein, which, in infected cells, forms a complex with two host transcription factors: octamer-binding protein 1 (Oct-1) and the transcriptional coregulator host cell factor 1 (HCF-1) (2-5). The VP16 -Oct-1-HCF-1 multiprotein complex binds to conserved core elements on IE gene promoters and recruits cellular transcription and chromatin-modifying factors to initiate high levels of viral gene expression (6-8). HCF-1 is essential for VP16-me...

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Section: Discussionmentioning

confidence: 99%

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

Angelova

Ortiz‐Meoz

Walker

et al. 2015

J Virol

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“…C. elegans also provides unique genetic advantages to study the effects of altered O-GlcNAc cycling; loss of function of Ogt in vertebrate systems results in embryonic lethality (24,25). However, C. elegans animals bearing null mutations of ogt-1 or oga-1 are alive and fertile and appear phenotypically wild type (WT) with respect to development, growth, and movement (26,27).…”

mentioning

confidence: 99%

O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases

Wang¹,

Lazarus²,

Forsythe³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the phenotype in transgenic models of tauopathy, amyloid β-peptide, and polyglutamine expansion. Intriguingly, loss of function of O-GlcNAc transferase alleviated, whereas loss of O-GlcNAcase enhanced, the phenotype of multiple neurodegenerative disease models. The O-GlcNAc cycling mutants act in part by altering DAF-16 – dependent transcription and modulating the protein degradation machinery. These findings suggest that O-GlcNAc levels may directly influence neurodegenerative disease progression, thus making the enzymes of O-GlcNAc cycling attractive targets for neurodegenerative disease therapies.

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“…O-GlcNAcylation regulates a variety of vital cellular processes and is itself regulated developmentally in the brain (5). OGT knockout, which eliminates O-GlcNAcylation, results in embryonic lethality in vertebrates (6,7), indicating an essential role of O-GlcNAcylation during early development. Deregulation of O-GlcNAc modification has been linked to several human diseases, including neurodegenerative diseases (8)(9)(10).…”

mentioning

confidence: 99%

O-GlcNAc cycling modulates neurodegeneration

Chen

Liu

Iqbal

2012

Proc. Natl. Acad. Sci. U.S.A.

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O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development

Cited by 98 publications

References 87 publications

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases

O-GlcNAc cycling modulates neurodegeneration

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