The Relative Protein Abundance of UGT1A Alternative Splice Variants as a Key Determinant of Glucuronidation Activity In Vitro

Rouleau, Mélanie; Roberge, Jean; Falardeau, Sarah-Ann; Villeneuve, Lyne; Guillemette, Chantal

doi:10.1124/dmd.112.050468

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…To our knowledge, a similar phenomenon has never been observed for any other Golgi complex glycosyltransferase. Only one similar phenomenon has been observed for human UDP-glucuronosyltransferase enzymes (UGTs) and particularly for the UGT1A gene (62). Indeed, shorter UGT1A isoforms are deficient in glucuronic acid transferase activity and function as negative regulators of enzyme activity through protein-protein interactions.…”

Section: Discussionmentioning

confidence: 86%

Bovine Herpesvirus 4 Modulates Its β-1,6- N -Acetylglucosaminyltransferase Activity through Alternative Splicing

Lété

Markine-Goriaynoff

Machiels

et al. 2016

J Virol

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Carbohydrates play major roles in host-virus interactions. It is therefore not surprising that, during coevolution with their hosts, viruses have developed sophisticated mechanisms to hijack for their profit different pathways of glycan synthesis. Thus, the Bo17 gene of Bovine herpesvirus 4 (BoHV-4) encodes a homologue of the cellular core 2 protein ␤-1,6-N-acetylglucosaminyltransferase-mucin type (C2GnT-M), which is a key player for the synthesis of complex O-glycans. Surprisingly, we show in this study that, as opposed to what is observed for the cellular enzyme, two different mRNAs are encoded by the Bo17 gene of all available BoHV-4 strains. While the first one corresponds to the entire coding sequence of the Bo17 gene, the second results from the splicing of a 138-bp intron encoding critical residues of the enzyme. Antibodies generated against the Bo17 C terminus showed that the two forms of Bo17 are expressed in BoHV-4 infected cells, but enzymatic assays revealed that the spliced form is not active. In order to reveal the function of these two forms, we then generated recombinant strains expressing only the long or the short form of Bo17. Although we did not highlight replication differences between these strains, glycomic analyses and lectin neutralization assays confirmed that the splicing of the Bo17 gene gives the potential to BoHV-4 to fine-tune the global level of core 2 branching activity in the infected cell. Altogether, these results suggest the existence of new mechanisms to regulate the activity of glycosyltransferases from the Golgi apparatus. IMPORTANCEViruses are masters of adaptation that hijack cellular pathways to allow their growth. Glycans play a central role in many biological processes, and several studies have highlighted mechanisms by which viruses can affect glycosylation. Glycan synthesis is a nontemplate process regulated by the availability of key glycosyltransferases. Interestingly, bovine herpesvirus 4 encodes one such enzyme which is a key enzyme for the synthesis of complex O-glycans. In this study, we show that, in contrast to cellular homologues, this virus has evolved to alternatively express two proteins from this gene. While the first one is enzymatically active, the second results from the alternative splicing of the region encoding the catalytic site of the enzyme. We postulate that this regulatory mechanism could allow the virus to modulate the synthesis of some particular glycans for function at the location and/or the moment of infection.

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Section: Discussionmentioning

confidence: 86%

Bovine Herpesvirus 4 Modulates Its β-1,6- N -Acetylglucosaminyltransferase Activity through Alternative Splicing

Lété

Markine-Goriaynoff

Machiels

et al. 2016

J Virol

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Canadian Content in the Pages ofDrug Metabolism and Disposition: A Comprehensive Historical Analysis

Riddick

2023

Drug Metab Dispos

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A Comprehensive Bioinformatic Analysis of RNA-seq Datasets Reveals a Differential and Variable Expression of Wildtype and Variant UGT1A Transcripts in Human Tissues and Their Deregulation in Cancers

Hu,

Marri,

Hulin

et al. 2024

Cancers

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The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome.

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The Relative Protein Abundance of UGT1A Alternative Splice Variants as a Key Determinant of Glucuronidation Activity In Vitro

Cited by 3 publications

References 7 publications

Bovine Herpesvirus 4 Modulates Its β-1,6- N -Acetylglucosaminyltransferase Activity through Alternative Splicing

Bovine Herpesvirus 4 Modulates Its β-1,6- N -Acetylglucosaminyltransferase Activity through Alternative Splicing

Canadian Content in the Pages ofDrug Metabolism and Disposition: A Comprehensive Historical Analysis

A Comprehensive Bioinformatic Analysis of RNA-seq Datasets Reveals a Differential and Variable Expression of Wildtype and Variant UGT1A Transcripts in Human Tissues and Their Deregulation in Cancers

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