Divergent Expression and Metabolic Functions of Human Glucuronosyltransferases through Alternative Splicing.
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 in-frame 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.
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Michèle
M
Rouleau
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Alan
A
Tourancheau
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Camille
C
Girard-Bock
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Lyne
L
Villeneuve
Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada.
Jonathan
J
Vaucher
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Anne-Marie
AM
Duperré
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Yannick
Y
Audet-Delage
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada.
Isabelle
I
Gilbert
Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada.
Ion
I
Popa
Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada.
Arnaud
A
Droit
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec, QC G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada. Electronic address: chantal.guillemette@crchudequebec.ulaval.ca.
Chantal
C
Guillemette
D017398:Alternative Splicing; D000596:Amino Acids / Q000096:biosynthesis; D001681:Biological Assay; D002448:Cell Adhesion; D049109:Cell Proliferation; D015870:Gene Expression; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007422:Intestines / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D009711:Nucleotides / Q000096:biosynthesis; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
D000596:Amino Acids; D007527:Isoenzymes; D009711:Nucleotides; D012333:RNA, Messenger; D014453:Glucuronosyltransferase
Glucuronosyltransferase (UGT); RNA sequencing; alternative splicing; cell metabolism; drug metabolism; glucuronidation; transcriptome