Original Article

The Unfolded Protein Response Regulates Multiple Aspects of Secretory and Membrane Protein Biogenesis and Endoplasmic Reticulum Quality Control

Correspondence to: Davis T.W. Ng, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802. Tel:(814) 863-5686 Fax:(814) 863-5876 E-mail:dtn1{at}psu.edu.

The unfolded protein response (UPR) is an intracellular signaling pathway that relays signals from the lumen of the ER to activate target genes in the nucleus. We devised a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutants that are dependent on activation of the pathway for viability. Using this strategy, we isolated mutants affecting various aspects of ER function, including protein translocation, folding, glycosylation, glycosylphosphatidylinositol modification, and ER-associated protein degradation (ERAD). Extending results gleaned from the genetic studies, we demonstrate that the UPR regulates trafficking of proteins at the translocon to balance the needs of biosynthesis and ERAD. The approach also revealed connections of the UPR to other regulatory pathways. In particular, we identified SON1/RPN4, a recently described transcriptional regulator for genes encoding subunits of the proteasome. Our genetic strategy, therefore, offers a powerful means to provide insight into the physiology of the UPR and to identify novel genes with roles in many aspects of secretory and membrane protein biogenesis.

Key Words: protein translocation, protein maturation, gene regulation, glycosylation, protein degradation

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Zaugg, C., Monod, M., Weber, J., Harshman, K., Pradervand, S., Thomas, J., Bueno, M., Giddey, K., Staib, P. (2009). Gene Expression Profiling in the Human Pathogenic Dermatophyte Trichophyton rubrum during Growth on Proteins. Eukaryot Cell 8: 241-250 [Abstract] [Full Text]  
• Metzger, M. B., Michaelis, S. (2009). Analysis of Quality Control Substrates in Distinct Cellular Compartments Reveals a Unique Role for Rpn4p in Tolerating Misfolded Membrane Proteins. Mol. Biol. Cell 20: 1006-1019 [Abstract] [Full Text]  
• Cohen, T. J., Mallory, M. J., Strich, R., Yao, T.-P. (2008). Hos2p/Set3p Deacetylase Complex Signals Secretory Stress through the Mpk1p Cell Integrity Pathway. Eukaryot Cell 7: 1191-1199 [Abstract] [Full Text]  
• Wang, Q., Li, L., Ye, Y. (2008). Inhibition of p97-dependent Protein Degradation by Eeyarestatin I. J. Biol. Chem. 283: 7445-7454 [Abstract] [Full Text]  
• Parikh, B. A., Tortora, A., Li, X.-P., Tumer, N. E. (2008). Ricin Inhibits Activation of the Unfolded Protein Response by Preventing Splicing of the HAC1 mRNA. J. Biol. Chem. 283: 6145-6153 [Abstract] [Full Text]  
• Ju, D., Wang, X., Xu, H., Xie, Y. (2008). Genome-Wide Analysis Identifies MYND-Domain Protein Mub1 as an Essential Factor for Rpn4 Ubiquitylation. Mol. Cell. Biol. 28: 1404-1412 [Abstract] [Full Text]  
• Hrizo, S. L., Gusarova, V., Habiel, D. M., Goeckeler, J. L., Fisher, E. A., Brodsky, J. L. (2007). The Hsp110 Molecular Chaperone Stabilizes Apolipoprotein B from Endoplasmic Reticulum-associated Degradation (ERAD). J. Biol. Chem. 282: 32665-32675 [Abstract] [Full Text]  
• Scott, C. M., Kruse, K. B., Schmidt, B. Z., Perlmutter, D. H., McCracken, A. A., Brodsky, J. L. (2007). ADD66, a Gene Involved in the Endoplasmic Reticulum-associated Degradation of {alpha}-1-Antitrypsin-Z in Yeast, Facilitates Proteasome Activity and Assembly. Mol. Biol. Cell 18: 3776-3787 [Abstract] [Full Text]  
• Sato, K., Noda, Y., Yoda, K. (2007). Pga1 Is an Essential Component of Glycosylphosphatidylinositol-Mannosyltransferase II of Saccharomyces cerevisiae. Mol. Biol. Cell 18: 3472-3485 [Abstract] [Full Text]  
• Maeda, Y., Tashima, Y., Houjou, T., Fujita, M., Yoko-o, T., Jigami, Y., Taguchi, R., Kinoshita, T. (2007). Fatty Acid Remodeling of GPI-anchored Proteins Is Required for Their Raft Association. Mol. Biol. Cell 18: 1497-1506 [Abstract] [Full Text]  
• Ahner, A., Nakatsukasa, K., Zhang, H., Frizzell, R. A., Brodsky, J. L. (2007). Small Heat-Shock Proteins Select {Delta}F508-CFTR for Endoplasmic Reticulum-associated Degradation. Mol. Biol. Cell 18: 806-814 [Abstract] [Full Text]  
• Yu, C.-Y., Hsu, Y.-W., Liao, C.-L., Lin, Y.-L. (2006). Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress. J. Virol. 80: 11868-11880 [Abstract] [Full Text]  
• Fujita, M., Umemura, M., Yoko-o, T., Jigami, Y. (2006). PER1 Is Required for GPI-Phospholipase A2 Activity and Involved in Lipid Remodeling of GPI-anchored Proteins. Mol. Biol. Cell 17: 5253-5264 [Abstract] [Full Text]  
• Fujita, M., Yoko-o, T., Jigami, Y. (2006). Inositol Deacylation by Bst1p Is Required for the Quality Control of Glycosylphosphatidylinositol-anchored Proteins. Mol. Biol. Cell 17: 834-850 [Abstract] [Full Text]  
• Subramanian, S., Woolford, C. A., Drill, E., Lu, M., Jones, E. W. (2006). Pbn1p: An essential endoplasmic reticulum membrane protein required for protein processing in the endoplasmic reticulum of budding yeast. Proc. Natl. Acad. Sci. USA 103: 939-944 [Abstract] [Full Text]  
• Kruse, K. B., Brodsky, J. L., McCracken, A. A. (2006). Characterization of an ERAD Gene as VPS30/ATG6 Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human {alpha}-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ. Mol. Biol. Cell 17: 203-212 [Abstract] [Full Text]  
• Jakobsen,, M. K., Poulsen,, L. R., Schulz,, A., Fleurat-Lessard,, P., Moller,, A., Husted,, S., Schiott,, M., Amtmann,, A., Palmgren,, M. G. (2005). Pollen development and fertilization in Arabidopsis is dependent on the MALE GAMETOGENESIS IMPAIRED ANTHERS gene encoding a Type V P-type ATPase. Genes Dev. 19: 2757-2769 [Abstract] [Full Text]  
• Huang, Z.-M., Tan, T., Yoshida, H., Mori, K., Ma, Y., Yen, T. S. B. (2005). Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress. Mol. Cell. Biol. 25: 7522-7533 [Abstract] [Full Text]  
• Kitiphongspattana, K., Mathews, C. E., Leiter, E. H., Gaskins, H. R. (2005). Proteasome Inhibition Alters Glucose-stimulated (Pro)insulin Secretion and Turnover in Pancreatic {beta}-Cells. J. Biol. Chem. 280: 15727-15734 [Abstract] [Full Text]  
• Spear, E. D., Ng, D. T.W. (2005). Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. JCB 169: 73-82 [Abstract] [Full Text]  
• Ramos-Castaneda, J., Park, Y.-n., Liu, M., Hauser, K., Rudolph, H., Shull, G. E., Jonkman, M. F., Mori, K., Ikeda, S., Ogawa, H., Arvan, P. (2005). Deficiency of ATP2C1, a Golgi Ion Pump, Induces Secretory Pathway Defects in Endoplasmic Reticulum (ER)-associated Degradation and Sensitivity to ER Stress. J. Biol. Chem. 280: 9467-9473 [Abstract] [Full Text]  
• Weber, K., Johnson, N., Champlin, D., Patty, A. (2005). Many P-Element Insertions Affect Wing Shape in Drosophila melanogaster. Genetics 169: 1461-1475 [Abstract] [Full Text]  
• Kim, A. J., Shi, Y., Austin, R. C., Werstuck, G. H. (2005). Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. J. Cell Sci. 118: 89-99 [Abstract] [Full Text]  
• Chang, H. J., Jesch, S. A., Gaspar, M. L., Henry, S. A. (2004). Role of the Unfolded Protein Response Pathway in Secretory Stress and Regulation of INO1 Expression in Saccharomyces cerevisiae. Genetics 168: 1899-1913 [Abstract] [Full Text]  
• Zhong, X., Shen, Y., Ballar, P., Apostolou, A., Agami, R., Fang, S. (2004). AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation. J. Biol. Chem. 279: 45676-45684 [Abstract] [Full Text]  
• Huyer, G., Piluek, W. F., Fansler, Z., Kreft, S. G., Hochstrasser, M., Brodsky, J. L., Michaelis, S. (2004). Distinct Machinery Is Required in Saccharomyces cerevisiae for the Endoplasmic Reticulum-associated Degradation of a Multispanning Membrane Protein and a Soluble Luminal Protein. J. Biol. Chem. 279: 38369-38378 [Abstract] [Full Text]  
• Ellis, C. D., Wang, F., MacDiarmid, C. W., Clark, S., Lyons, T., Eide, D. J. (2004). Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function. JCB 166: 325-335 [Abstract] [Full Text]  
• Imhof, I., Flury, I., Vionnet, C., Roubaty, C., Egger, D., Conzelmann, A. (2004). Glycosylphosphatidylinositol (GPI) Proteins of Saccharomyces cerevisiae Contain Ethanolamine Phosphate Groups on the {alpha}1,4-linked Mannose of the GPI Anchor. J. Biol. Chem. 279: 19614-19627 [Abstract] [Full Text]  
• Eguez, L., Chung, Y.-S., Kuchibhatla, A., Paidhungat, M., Garrett, S. (2004). Yeast Mn2+ Transporter, Smf1p, Is Regulated by Ubiquitin-Dependent Vacuolar Protein Sorting. Genetics 167: 107-117 [Abstract] [Full Text]  
• Coughlan, C. M., Walker, J. L., Cochran, J. C., Wittrup, K. D., Brodsky, J. L. (2004). Degradation of Mutated Bovine Pancreatic Trypsin Inhibitor in the Yeast Vacuole Suggests Post-endoplasmic Reticulum Protein Quality Control. J. Biol. Chem. 279: 15289-15297 [Abstract] [Full Text]  
• Proszynski, T. J., Simons, K., Bagnat, M. (2004). O-Glycosylation as a Sorting Determinant for Cell Surface Delivery in Yeast. Mol. Biol. Cell 15: 1533-1543 [Abstract] [Full Text]  
• Huyer, G., Longsworth, G. L., Mason, D. L., Mallampalli, M. P., McCaffery, J. M., Wright, R. L., Michaelis, S. (2004). A Striking Quality Control Subcompartment in Saccharomyces cerevisiae: The Endoplasmic Reticulum-associated Compartment. Mol. Biol. Cell 15: 908-921 [Abstract] [Full Text]  
• Chavan, M., Suzuki, T., Rekowicz, M., Lennarz, W. (2003). Genetic, biochemical, and morphological evidence for the involvement of N-glycosylation in biosynthesis of the cell wall {beta}1,6-glucan of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 100: 15381-15386 [Abstract] [Full Text]  
• Yamamoto, K., Hamada, H., Shinkai, H., Kohno, Y., Koseki, H., Aoe, T. (2003). The KDEL Receptor Modulates the Endoplasmic Reticulum Stress Response through Mitogen-activated Protein Kinase Signaling Cascades. J. Biol. Chem. 278: 34525-34532 [Abstract] [Full Text]  
• Trombetta, E. S. (2003). The contribution of N-glycans and their processing in the endoplasmic reticulum to glycoprotein biosynthesis. Glycobiology 13: 77R-91R [Abstract] [Full Text]  
• Kabani, M., Kelley, S. S., Morrow, M. W., Montgomery, D. L., Sivendran, R., Rose, M. D., Gierasch, L. M., Brodsky, J. L. (2003). Dependence of Endoplasmic Reticulum-associated Degradation on the Peptide Binding Domain and Concentration of BiP. Mol. Biol. Cell 14: 3437-3448 [Abstract] [Full Text]  
• Spear, E. D., Ng, D. T.W. (2003). Stress Tolerance of Misfolded Carboxypeptidase Y Requires Maintenance of Protein Trafficking and Degradative Pathways. Mol. Biol. Cell 14: 2756-2767 [Abstract] [Full Text]  
• Palmer, E. A., Kruse, K. B., Fewell, S. W., Buchanan, S. M., Brodsky, J. L., McCracken, A. A. (2003). Differential requirements of novel A1PiZ degradation deficient (ADD) genes in ER-associated protein degradation. J. Cell Sci. 116: 2361-2373 [Abstract] [Full Text]  
• Kroesen, B.-J., Jacobs, S., Pettus, B. J., Sietsma, H., Kok, J. W., Hannun, Y. A., de Leij, L. F. M. H. (2003). BcR-induced Apoptosis Involves Differential Regulation of C16 and C24-Ceramide Formation and Sphingolipid-dependent Activation of the Proteasome. J. Biol. Chem. 278: 14723-14731 [Abstract] [Full Text]  
• Valkonen, M., Penttila, M., Saloheimo, M. (2003). Effects of Inactivation and Constitutive Expression of the Unfolded- Protein Response Pathway on Protein Production in the Yeast Saccharomyces cerevisiae. Appl. Environ. Microbiol. 69: 2065-2072 [Abstract] [Full Text]  
• Kwak, M.-K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., Kensler, T. W. (2003). Modulation of Gene Expression by Cancer Chemopreventive Dithiolethiones through the Keap1-Nrf2 Pathway. IDENTIFICATION OF NOVEL GENE CLUSTERS FOR CELL SURVIVAL. J. Biol. Chem. 278: 8135-8145 [Abstract] [Full Text]  
• Vashist, S., Frank, C. G., Jakob, C. A., Ng, D. T.W. (2002). Two Distinctly Localized P-Type ATPases Collaborate to Maintain Organelle Homeostasis Required for Glycoprotein Processing and Quality Control. Mol. Biol. Cell 13: 3955-3966 [Abstract] [Full Text]  
• Ko, H. S., Uehara, T., Nomura, Y. (2002). Role of Ubiquilin Associated with Protein-disulfide Isomerase in the Endoplasmic Reticulum in Stress-induced Apoptotic Cell Death. J. Biol. Chem. 277: 35386-35392 [Abstract] [Full Text]  
• Chang, H. J., Jones, E. W., Henry, S. A. (2002). Role of the Unfolded Protein Response Pathway in Regulation of INO1 and in the sec14 Bypass Mechanism in Saccharomyces cerevisiae. Genetics 162: 29-43 [Abstract] [Full Text]  
• Urano, F., Calfon, M., Yoneda, T., Yun, C., Kiraly, M., Clark, S. G., Ron, D. (2002). A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response. JCB 158: 639-646 [Abstract] [Full Text]  
• Yoneda, T., Urano, F., Ron, D. (2002). Transmission of proteotoxicity across cellular compartments. Genes Dev. 16: 1307-1313 [Full Text]  
• Sagt, C. M. J., Muller, W. H., van der Heide, L., Boonstra, J., Verkleij, A. J., Verrips, C. T. (2002). Impaired Cutinase Secretion in Saccharomyces cerevisiae Induces Irregular Endoplasmic Reticulum (ER) Membrane Proliferation, Oxidative Stress, and ER-Associated Degradation. Appl. Environ. Microbiol. 68: 2155-2160 [Abstract] [Full Text]  
• SUZUKI, T., PARK, H., LENNARZ, W. J. (2002). Cytoplasmic peptide:N-glycanase (PNGase) in eukaryotic cells: occurrence, primary structure, and potential functions. FASEB J. 16: 635-641 [Abstract] [Full Text]  
• Spiliotis, E. T., Pentcheva, T., Edidin, M. (2002). Probing for Membrane Domains in the Endoplasmic Reticulum: Retention and Degradation of Unassembled MHC Class I Molecules. Mol. Biol. Cell 13: 1566-1581 [Abstract] [Full Text]  
• Bays, N. W., Wilhovsky, S. K., Goradia, A., Hodgkiss-Harlow, K., Hampton, R. Y. (2001). HRD4/NPL4 Is Required for the Proteasomal Processing of Ubiquitinated ER Proteins. Mol. Biol. Cell 12: 4114-4128 [Abstract] [Full Text]  
• Vashist, S., Kim, W., Belden, W. J., Spear, E. D., Barlowe, C., Ng, D. T.W. (2001). Distinct retrieval and retention mechanisms are required for the quality control of endoplasmic reticulum protein folding. JCB 155: 355-368 [Abstract] [Full Text]  
• Hitchcock, A. L., Krebber, H., Frietze, S., Lin, A., Latterich, M., Silver, P. A. (2001). The Conserved Npl4 Protein Complex Mediates Proteasome-dependent Membrane-bound Transcription Factor Activation. Mol. Biol. Cell 12: 3226-3241 [Abstract] [Full Text]  
• Kondylis, V., Goulding, S. E., Dunne, J. C., Rabouille, C. (2001). Biogenesis of Golgi Stacks in Imaginal Discs of Drosophila melanogaster. Mol. Biol. Cell 12: 2308-2327 [Abstract] [Full Text]  
• Zhang, Y., Nijbroek, G., Sullivan, M. L., McCracken, A. A., Watkins, S. C., Michaelis, S., Brodsky, J. L. (2001). Hsp70 Molecular Chaperone Facilitates Endoplasmic Reticulum-associated Protein Degradation of Cystic Fibrosis Transmembrane Conductance Regulator in Yeast. Mol. Biol. Cell 12: 1303-1314 [Abstract] [Full Text]  
• Caldwell, S. R., Hill, K. J., Cooper, A. A. (2001). Degradation of Endoplasmic Reticulum (ER) Quality Control Substrates Requires Transport between the ER and Golgi. J. Biol. Chem. 276: 23296-23303 [Abstract] [Full Text]  
• Teckman, J. H., Burrows, J., Hidvegi, T., Schmidt, B., Hale, P. D., Perlmutter, D. H. (2001). The Proteasome Participates in Degradation of Mutant alpha 1-Antitrypsin Z in the Endoplasmic Reticulum of Hepatoma-derived Hepatocytes. J. Biol. Chem. 276: 44865-44872 [Abstract] [Full Text]  
• Umebayashi, K., Fukuda, R., Hirata, A., Horiuchi, H., Nakano, A., Ohta, A., Takagi, M. (2001). Activation of the Ras-cAMP Signal Transduction Pathway Inhibits the Proteasome-independent Degradation of Misfolded Protein Aggregates in the Endoplasmic Reticulum Lumen. J. Biol. Chem. 276: 41444-41454 [Abstract] [Full Text]  
• Lehrman, M. A. (2001). Oligosaccharide-based Information in Endoplasmic Reticulum Quality Control and Other Biological Systems. J. Biol. Chem. 276: 8623-8626 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents