Genomewide Analysis Reveals Novel Pathways Affecting Endoplasmic Reticulum Homeostasis, Protein Modification and Quality Control

• Published in: Genetics (Austin) 2009-07, Vol.182 (3), p.757-769
• Main Authors: Copic, Alenka, Dorrington, Mariana, Pagant, Silvere, Barry, Justine, Lee, Marcus C.S, Singh, Indira, Hartman, John L. IV, Miller, Elizabeth A
• Format: Article
• Language: English
• Subjects: Acetylation; chromatin remodeling; Cystic fibrosis; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fatty acids; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; genome; Genome, Fungal; genomics; Glycosylation; Golgi Apparatus - metabolism; histones; Histones - genetics; Histones - metabolism; homeostasis; Homeostasis - physiology; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Immunoblotting; Immunoprecipitation; Investigations; Models, Biological; molecular chaperones; mutants; Mutation; phenotype; Protein Folding; Protein Processing, Post-Translational - physiology; protein transport; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Residents; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; yeasts
• ISSN: 0016-6731; 1943-2631; 1943-2631
• DOI: 10.1534/genetics.109.101105

To gain new mechanistic insight into ER homeostasis and the biogenesis of secretory proteins, we screened a genomewide collection of yeast mutants for defective intracellular retention of the ER chaperone, Kar2p. We identified 87 Kar2p-secreting strains, including a number of known components in secretory protein modification and sorting. Further characterization of the 73 nonessential Kar2p retention mutants revealed roles for a number of novel gene products in protein glycosylation, GPI-anchor attachment, ER quality control, and retrieval of escaped ER residents. A subset of these mutants, required for ER retrieval, included the GET complex and two novel proteins that likely function similarly in membrane insertion of tail-anchored proteins. Finally, the variant histone, Htz1p, and its acetylation state seem to play an important role in maintaining ER retrieval pathways, suggesting a surprising link between chromatin remodeling and ER homeostasis.