De-Souza Evandro A, Pimentel Felipe S A, Machado Caio M, Martins Larissa S, da-Silva Wagner S, Montero-Lomelí Mónica, Masuda Claudio A
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.
Dis Model Mech. 2014 Jan;7(1):55-61. doi: 10.1242/dmm.012641. Epub 2013 Sep 25.
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.
经典型半乳糖血症是一种人类常染色体隐性疾病，由GALT基因（酵母中的GAL7）突变引起，该基因编码半乳糖-1-磷酸尿苷转移酶。我们在此表明，在半乳糖血症的两种酵母模型中，未折叠蛋白反应途径由半乳糖触发：锂处理的细胞和gal7Δ突变体。在这些条件下，半乳糖-1-磷酸的合成对于触发未折叠蛋白反应至关重要，因为编码半乳糖激酶的基因GAL1的缺失完全消除了未折叠蛋白反应的激活和半乳糖毒性。两种酵母模型中未折叠蛋白反应的受损使细胞对半乳糖更加敏感，从而揭示了其细胞毒性作用。这些结果表明，在半乳糖血症条件下会诱导内质网应激，并强调了未折叠蛋白反应途径在这些经典型半乳糖血症模型中对细胞适应的重要性。
