Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment

doi:10.1083/jcb.131.6.1403

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Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment

G Raposo, HM van Santen, R Leijendekker, HJ Geuze and HL Ploegh
Universiteit Utrecht, Faculty of Medicine, Department of Cell Biology, The Netherlands.

Misfolded membrane proteins are rapidly degraded, often shortly after their synthesis and insertion in the endoplasmic reticulum (ER), but the exact location and mechanisms of breakdown remain unclear. We have exploited the requirement of MHC class I molecules for peptide to achieve their correct conformation: peptide can be withheld by introducing a null mutation for the MHC-encoded peptide transporter, TAP. By withholding TAP-dependent peptides, the vast majority of newly synthesized class I molecules fails to leave the endoplasmic reticulum and is degraded. We used mice transgenic for HLA-B27 on a TAP1- deficient background to allow visualization by immunoelectron microscopy of misfolded HLA-B27 molecules in thymic epithelial cells. In such HLA transgenic animals, the TAP mutation can be considered a genetic switch that allows control over the extent of folding of the protein of interest, HLA-B27, while the rate of synthesis of the constituent subunits remains unaltered. In TAP1-deficient, HLA-B27 transgenic animals, HLA-B27 molecules fail to assemble correctly, and do not undergo carbohydrate modifications associated with the Golgi apparatus, such as conversion to Endoglycosidase H resistance, and acquisition of sialic acids. We show that such molecules accumulate in an expanded network of tubular and fenestrated membranes. This compartment has its counterpart in normal thymic epithelial cells, and is identified as an ER-Golgi intermediate. We detect the presence of ubiquitin and ubiquitin-conjugating enzymes in association with this compartment, suggesting a nonlysosomal mode of degradation of its contents.
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Breuza, L., Halbeisen, R., Jeno, P., Otte, S., Barlowe, C., Hong, W., Hauri, H.-P. (2004). Proteomics of Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) Membranes from Brefeldin A-treated HepG2 Cells Identifies ERGIC-32, a New Cycling Protein That Interacts with Human Erv46. J. Biol. Chem. 279: 47242-47253 [Abstract] [Full Text]
Tran, T. M., Satumtira, N., Dorris, M. L., May, E., Wang, A., Furuta, E., Taurog, J. D. (2004). HLA-B27 in Transgenic Rats Forms Disulfide-Linked Heavy Chain Oligomers and Multimers That Bind to the Chaperone BiP. J. Immunol. 172: 5110-5119 [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]
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]
Park, B., Ahn, K. (2003). An Essential Function of Tapasin in Quality Control of HLA-G Molecules. J. Biol. Chem. 278: 14337-14345 [Abstract] [Full Text]
Tirosh, B., Furman, M. H., Tortorella, D., Ploegh, H. L. (2003). Protein Unfolding Is Not a Prerequisite for Endoplasmic Reticulum-to-Cytosol Dislocation. J. Biol. Chem. 278: 6664-6672 [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]
Halaban, R., Patton, R. S., Cheng, E., Svedine, S., Trombetta, E. S., Wahl, M. L., Ariyan, S., Hebert, D. N. (2002). Abnormal Acidification of Melanoma Cells Induces Tyrosinase Retention in the Early Secretory Pathway. J. Biol. Chem. 277: 14821-14828 [Abstract] [Full Text]
Yu, Y. Y. L., Netuschil, N., Lybarger, L., Connolly, J. M., Hansen, T. H. (2002). Cutting Edge: Single-Chain Trimers of MHC Class I Molecules Form Stable Structures That Potently Stimulate Antigen-Specific T Cells and B Cells. J. Immunol. 168: 3145-3149 [Abstract] [Full Text]
Graves, T. K., Patel, S., Dannies, P. S., Hinkle, P. M. (2002). Misfolded growth hormone causes fragmentation of the Golgi apparatus and disrupts endoplasmic reticulum-to-Golgi traffic. J. Cell Sci. 114: 3685-3694 [Abstract] [Full Text]
Luft, T., Rizkalla, M., Tai, T. Y., Chen, Q., MacFarlan, R. I., Davis, I. D., Maraskovsky, E., Cebon, J. (2001). Exogenous Peptides Presented by Transporter Associated with Antigen Processing (TAP)-Deficient and TAP-Competent Cells: Intracellular Loading and Kinetics of Presentation. J. Immunol. 167: 2529-2537 [Abstract] [Full Text]
Chun, T., Grandea, A. G. III, Lybarger, L., Forman, J., Van Kaer, L., Wang, C.-R. (2001). Functional Roles of TAP and Tapasin in the Assembly of M3-N-Formylated Peptide Complexes. J. Immunol. 167: 1507-1514 [Abstract] [Full Text]
Kamhi-Nesher, S., Shenkman, M., Tolchinsky, S., Fromm, S. V., Ehrlich, R., Lederkremer, G. Z. (2001). A Novel Quality Control Compartment Derived from the Endoplasmic Reticulum. Mol. Biol. Cell 12: 1711-1723 [Abstract] [Full Text]
Owen, B. A. L., Pease, L. R. (2001). Thermal Stability of MHC Class I-{{beta}}2-Microglobulin Peptide Complexes in the Endoplasmic Reticulum Is Determined by the Peptide Occupancy of the Transporter Associated with Antigen Processing Complex. J. Immunol. 166: 1740-1747 [Abstract] [Full Text]
Teckman, J. H., Perlmutter, D. H. (2000). Retention of mutant alpha 1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G961-G974 [Abstract] [Full Text]
Allen, R. L., O'Callaghan, C. A., McMichael, A. J., Bowness, P. (1999). Cutting Edge: HLA-B27 Can Form a Novel {beta}2-Microglobulin-Free Heavy Chain Homodimer Structure. J. Immunol. 162: 5045-5048 [Abstract] [Full Text]
Owen, B. A. L., Pease, L. R. (1999). TAP Association Influences the Conformation of Nascent MHC Class I Molecules. J. Immunol. 162: 4677-4684 [Abstract] [Full Text]
White, A. L., Guerra, B., Wang, J., Lanford, R. E. (1999). Presecretory degradation of apolipoprotein[a] is mediated by the proteasome pathway. J. Lipid Res. 40: 275-286 [Abstract] [Full Text]
Ostedgaard, L., Zeiher, B, Welsh, M. (1999). Processing of CFTR bearing the P574H mutation differs from wild-type and deltaF508-CFTR. J. Cell Sci. 112: 2091-2098 [Abstract]
Greenfield, J., High, S (1999). The Sec61 complex is located in both the ER and the ER-Golgi intermediate compartment. J. Cell Sci. 112: 1477-1486 [Abstract]
Mitchell, D. M., Zhou, M., Pariyarath, R., Wang, H., Aitchison, J. D., Ginsberg, H. N., Fisher, E. A. (1998). Apoprotein B100 has a prolonged interaction with the translocon during which its lipidation and translocation change from dependence on the microsomal triglyceride transfer protein to independence. Proc. Natl. Acad. Sci. USA 95: 14733-14738 [Abstract] [Full Text]
Cardinali, G., Gentile, M., Cirone, M., Zompetta, C., Frati, L., Faggioni, A., Torrisi, M. R. (1998). Viral Glycoproteins Accumulate in Newly Formed Annulate Lamellae following Infection of Lymphoid Cells by Human Herpesvirus 6. J. Virol. 72: 9738-9746 [Abstract] [Full Text]
Hobman, T. C., Zhao, B., Chan, H., Farquhar, M. G. (1998). Immunoisolation and Characterization of a Subdomain of the Endoplasmic Reticulum That Concentrates Proteins Involved in COPII Vesicle Biogenesis. Mol. Biol. Cell 9: 1265-1278 [Abstract] [Full Text]
Dusseljee, S, Wubbolts, R, Verwoerd, D, Tulp, A, Janssen, H, Calafat, J, Neefjes, J (1998). Removal and degradation of the free MHC class II beta chain in the endoplasmic reticulum requires proteasomes and is accelerated by BFA. J. Cell Sci. 111: 2217-2226 [Abstract]
Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., Sly, W. S. (1997). Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with beta 2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7�cells. Proc. Natl. Acad. Sci. USA 94: 12384-12389 [Abstract] [Full Text]
Shenkman, M., Ayalon, M., Lederkremer, G. Z. (1997). Endoplasmic reticulum quality control of asialoglycoprotein receptor H2a involves a determinant for retention and not�retrieval. Proc. Natl. Acad. Sci. USA 94: 11363-11368 [Abstract] [Full Text]
Fisher, E. A., Zhou, M., Mitchell, D. M., Wu, X., Omura, S., Wang, H., Goldberg, A. L., Ginsberg, H. N. (1997). The Degradation of Apolipoprotein B100 Is Mediated by the Ubiquitin-proteasome Pathway and Involves Heat Shock Protein 70. J. Biol. Chem. 272: 20427-20434 [Abstract] [Full Text]
Meerovitch, K., Wing, S., Goltzman, D. (1997). Preproparathyroid Hormone-related Protein, a Secreted Peptide, Is a Substrate for the Ubiquitin Proteolytic System. J. Biol. Chem. 272: 6706-6713 [Abstract] [Full Text]
Hughes, E. A., Hammond, C., Cresswell, P. (1997). Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by�the�proteasome. Proc. Natl. Acad. Sci. USA 94: 1896-1901 [Abstract] [Full Text]
Adeli, K., Wettesten, M., Asp, L., Mohammadi, A., Macri, J., Olofsson, S.-O. (1997). Intracellular Assembly and Degradation of Apolipoprotein B-100-containing Lipoproteins in Digitonin-permeabilized HEP G2 Cells. J. Biol. Chem. 272: 5031-5039 [Abstract] [Full Text]
Wang, H., Benlimame, N, Nabi, I (1997). The AMF-R tubule is a smooth ilimaquinone-sensitive subdomain of the endoplasmic reticulum. J. Cell Sci. 110: 3043-3053 [Abstract]
Moolenaar, C., Ouwendijk, J, Wittpoth, M, Wisselaar, H., Hauri, H., Ginsel, L., Naim, H., Fransen, J. (1997). A mutation in a highly conserved region in brush-border sucrase-isomaltase and lysosomal alpha-glucosidase results in Golgi retention. J. Cell Sci. 110: 557-567 [Abstract]
Qu, D., Teckman, J. H., Omura, S., Perlmutter, D. H. (1996). Degradation of a Mutant Secretory Protein, alpha 1-Antitrypsin Z, in the Endoplasmic Reticulum Requires Proteasome Activity. J. Biol. Chem. 271: 22791-22795 [Abstract] [Full Text]
Yamamoto, A, Masaki, R, Tashiro, Y (1996). Formation of crystalloid endoplasmic reticulum in COS cells upon overexpression of microsomal aldehyde dehydrogenase by cDNA transfection. J. Cell Sci. 109: 1727-1738 [Abstract]
Bubeck, A., Reusch, U., Wagner, M., Ruppert, T., Muranyi, W., Kloetzel, P. M., Koszinowski, U. H. (2002). The Glycoprotein gp48 of Murine Cytomegalovirus. PROTEASOME-DEPENDENT CYTOSOLIC DISLOCATION AND DEGRADATION. J. Biol. Chem. 277: 2216-2224 [Abstract] [Full Text]
Khanna, R., Myers, M. P., Laine, M., Papazian, D. M. (2001). Glycosylation Increases Potassium Channel Stability and Surface Expression in Mammalian Cells. J. Biol. Chem. 276: 34028-34034 [Abstract] [Full Text]
Zuber, C., Fan, J.-y., Guhl, B., Parodi, A., Fessler, J. H., Parker, C., Roth, J. (2001). Immunolocalization of UDP-glucose:glycoprotein glucosyltransferase indicates involvement of pre-Golgi intermediates in protein quality control. Proc. Natl. Acad. Sci. USA 98: 10710-10715 [Abstract] [Full Text]