The unfolded protein response is necessary but not sufficient to compensate for defects in disulfide isomerization.
Pdi1p (protein-disulfide isomerase) is a folding assistant of the endoplasmic reticulum (ER) that catalyzes disulfide formation and the isomerization of incorrect disulfides. Its disulfide forming activity is its essential function in Saccharomyces cerevisiae. A truncation mutant (Pdi1a') that is competent in disulfide formation but deficient in catalyzing isomerization has only a small effect on growth, although the maturation of isomerase-requiring substrates (carboxypeptidase Y) is impaired (Xiao, R., Wilkinson, B., Solovyov, A., Winther, J. R., Holmgren, A., Lundstrom-Ljung, J., and Gilbert, H. F. (2004) J. Biol. Chem. 279, 49780-49786). We show here that there are multiple ways to compensate for defects in disulfide formation and isomerization in the ER. Genes of the unfolded protein response are induced, and deletions of the nonessential IRE1 or HAC1 genes are synthetically lethal. Diploid synthetic lethality analysis by microarray (dSLAM) using PDIa' and a temperature-sensitive mutant of PDIa' as query mutations reveals a group of 130 synthetically lethal genes. Only 10 of these correspond to genes clearly associated with the unfolded protein response. More than half are involved in vesicle traffic, not only out of and into the ER but anterograde and retrograde traffic from most cellular compartments. This suggests that defects in protein maturation in one intracellular compartment may be compensated for by adjusting vesicular traffic patterns throughout the cell.
Kim
Jai-Hyun
JH
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Houston, Texas, USA.
Zhao
Yinsuo
Y
Pan
Xuewen
X
He
Xiangwei
X
Gilbert
Hiram F
HF
D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D004220:Disulfides / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D007536:Isomerism; D008562:Membrane Glycoproteins / Q000235:genetics; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; D004220:Disulfides; C091341:HAC1 protein, S cerevisiae; D008562:Membrane Glycoproteins; C080576:PDI1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D019704:Protein Disulfide-Isomerases