The unfolded protein response has a protective role in yeast models of classic galactosemia

Evandro A De-Souza; Felipe S A Pimentel; Caio M Machado; Larissa S Martins; Wagner S da-Silva; Mónica Montero-Lomelí; Claudio A Masuda

doi:10.1242/dmm.012641

The unfolded protein response has a protective role in yeast models of classic galactosemia

Dis Model Mech. 2014 Jan;7(1):55-61. doi: 10.1242/dmm.012641. Epub 2013 Sep 25.

Authors

Evandro A De-Souza¹, Felipe S A Pimentel, Caio M Machado, Larissa S Martins, Wagner S da-Silva, Mónica Montero-Lomelí, Claudio A Masuda

Affiliation

¹ 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.

Abstract

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.

Keywords: Galactose; Galactosemia; Lithium; UPR; Yeast.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing
Basic-Leucine Zipper Transcription Factors / metabolism
Endoplasmic Reticulum / metabolism
Fungal Proteins / metabolism
Galactokinase / metabolism
Galactose / metabolism
Galactosemias / enzymology*
Galactosemias / genetics*
Galactosephosphates / chemistry
Gene Expression Regulation, Fungal*
Glycoproteins / metabolism
HSP70 Heat-Shock Proteins / metabolism
Humans
Mutation / drug effects
Oxidoreductases Acting on Sulfur Group Donors / metabolism
Protein Folding
RNA, Messenger / metabolism
Repressor Proteins / metabolism
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins / metabolism
Unfolded Protein Response*

Substances

Basic-Leucine Zipper Transcription Factors
Fungal Proteins
Galactosephosphates
Glycoproteins
HAC1 protein, S cerevisiae
HSP70 Heat-Shock Proteins
KAR2 protein, yeast
RNA, Messenger
Repressor Proteins
Saccharomyces cerevisiae Proteins
galactose-1-phosphate
Oxidoreductases Acting on Sulfur Group Donors
ERO1 protein, S cerevisiae
Galactokinase
Galactose