The unfolded protein response has a protective role in yeast models of classic galactosemia.
Classic galactosemia is a human autosomal recessive disorder caused by mutations in the GALT gene (GAL7 in yeast), which encodes the enzyme galactose-1-phosphate uridyltransferase. Here we show that the unfolded protein response pathway is triggered by galactose in two yeast models of galactosemia: lithium-treated cells and the gal7Δ mutant. The synthesis of galactose-1-phosphate is essential to trigger the unfolded protein response under these conditions because the deletion of the galactokinase-encoding gene GAL1 completely abolishes unfolded protein response activation and galactose toxicity. Impairment of the unfolded protein response in both yeast models makes cells even more sensitive to galactose, unmasking its cytotoxic effect. These results indicate that endoplasmic reticulum stress is induced under galactosemic conditions and underscores the importance of the unfolded protein response pathway to cellular adaptation in these models of classic galactosemia.
Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil.
Evandro A
EA
De-Souza
Felipe S A
FS
Pimentel
Caio M
CM
Machado
Larissa S
LS
Martins
Wagner S
WS
da-Silva
Mónica
M
Montero-Lomelí
Claudio A
CA
Masuda
D017398:Alternative Splicing; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism; D005686:Galactokinase / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D005693:Galactosemias / Q000201:enzymology* / Q000235:genetics*; D005695:Galactosephosphates / Q000737:chemistry; D015966:Gene Expression Regulation, Fungal; D006023:Glycoproteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D056811:Unfolded Protein Response
D050976:Basic-Leucine Zipper Transcription Factors; D005656:Fungal Proteins; D005695:Galactosephosphates; D006023:Glycoproteins; C091341:HAC1 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C029973:galactose-1-phosphate; D050862:Oxidoreductases Acting on Sulfur Group Donors; C113186:ERO1 protein, S cerevisiae; D005686:Galactokinase; D005690:Galactose
Galactose; Galactosemia; Lithium; UPR; Yeast