Journal
CELL REPORTS
Volume 17, Issue 1, Pages 114-124Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.08.077
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Funding
- Canadian Institutes for Health Research [MOP-42392, MOP-142318]
- Natural Sciences and Engineering Research Council of Canada [342176-2012]
- Canadian Research Chair in Pharmacogenomics
- Faculty of Pharmacy of Laval University
- Centre de Recherche en Endocrinologie Moleculaire et Oncologique et Genomique Humaine, Laval University
- Fonds de Recherche du Quebec - Sante
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Maintenance of cellular homeostasis and xenobiotic detoxification is mediated by 19 human UDP-glucuronosyltransferase enzymes (UGTs) encoded by ten genes that comprise the glucuronidation pathway. Deep RNA sequencing of major metabolic organs exposes a substantial expansion of the UGT transcriptome by alternative splicing, with variants representing 20% to 60% of canonical transcript expression. Nearly a fifth of expressed variants comprise inframe sequences that may create distinct structural and functional features. Follow-up cell-based assays reveal biological functions for these alternative UGT proteins. Some isoforms were found to inhibit or induce inactivation of drugs and steroids in addition to perturbing global cell metabolism (energy, amino acids, nucleotides), cell adhesion, and proliferation. This work highlights the biological relevance of alternative UGT expression, which we propose increases protein diversity through the evolution of metabolic regulators from specific enzymes.
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