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Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane

Nature Cell Biology volume 16, pages 77–86 (2014)Cite this article

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Abstract

Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD ligase) and degraded by cytosolic 26S proteasomes. The movement of these proteins through the lipid bilayer is assumed to occur via a protein-conducting channel of unknown nature. We show that the integral membrane protein Der1 oligomerizes, which relies on its interaction with the scaffolding protein Usa1. Mutations in the transmembrane domains of Der1 block the passage of soluble proteins across the ER membrane. As determined by site-specific photocrosslinking, the ER-luminal exposed parts of Der1 are in spatial proximity to the substrate receptor Hrd3, whereas the membrane-embedded domains reside adjacent to the ubiquitin ligase Hrd1. Intriguingly, both regions also form crosslinks to client proteins. Our data imply that Der1 initiates the export of aberrant polypeptides from the ER lumen by threading such molecules into the ER membrane and routing them to Hrd1 for ubiquitylation.

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Figure 1: The C terminus of Der1 is required for oligomerization and integration into the HRD ligase.
Figure 2: Mutations in the transmembrane domains of Der1 abolish the dislocation of luminal ERAD substrates.
Figure 3: pBpa-labelled Der1 forms crosslinks with components of the HRD ligase.
Figure 4: The pBpa-labelled Der1 variants are properly integrated into the HRD ligase.
Figure 5: pBpa–Der1 crosslinks to luminal ERAD substrates.
Figure 6: Dislocation-deficient point mutants of Der1 affect the crosslinking to HRD ligase components and CPY*–HA.
Figure 7: A model for the function of Der1 in the dislocation of ERAD substrates.

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Acknowledgements

The authors wish to thank the members of the laboratory for helpful and stimulating discussions, unpublished data and materials. We thank C. Volkwein for excellent technical assistance. We would like to thank P. G. Schultz (Scripps Research Institute, USA) for materials needed for the in vivo crosslinking experiments. T. A. Rapoport (Harvard Medical School, USA), D. H. Wolf (University of Stuttgart, Germany) and R. Y. Hampton (University of California, USA) are acknowledged for providing antibodies and plasmids. The Deutsche Forschungsgemeinschaft generously supports T.S. and E.J. (JA 1830/1-2, SFB 740, Priority Program 1365, and the German-Israel Project Cooperation DIP).

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Authors and Affiliations

  1. Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin-Buch, Germany

    Martin Mehnert, Thomas Sommer & Ernst Jarosch

  2. Humboldt-University Berlin, Institute of Biology, Invalidenstraße 43, 10115 Berlin, Germany

    Thomas Sommer

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Contributions

M.M. performed all experiments except Supplementary Fig. 2a and Supplementary Fig. 3c (E.J.). The experiments were designed by M.M. and E.J. T.S. guided the project planning. M.M. and E.J. wrote the manuscript.

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Correspondence to Thomas Sommer or Ernst Jarosch.

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Integrated supplementary information

Supplementary Figure 1 The carboxyterminus integrates Der1 into the HRD-ligase.

a, Sequence alignment of yeast Der1 with homologues in other organisms, generated by ClustalW and Jalview. Derlin-1 from Homo sapiens (hs, UniProtKB accession number Q9BUN8), Caenorhabditis elegans (ce, Q93561), Derlin-2 from Homo sapiens (hs, Q9GZP9), Caenorhabditis elegans(ce, Q21997), Derlin-3 from Homo sapiens (hs, Q96Q80), Mus Musculus (mm, Q9D8K3), Der1 from Saccharomyces cerevisiae (sc, P38307). The position of the Der1 transmembrane segments as predicted by hydrophobicity calculations and biochemical analysis by Hitt et al.16 is given by green bars. Of note, in an alternative model for Derlin-1 topology proposed by Greenblatt et al. 32, the position of transmembrane segments one and two is almost identical. Black diamonds label amino acids in Der1, which were subjected to site-directed mutagenesis (Supplementary Table 1). b, Cycloheximide decay assay to monitor the degradation of Der1 in strains of the indicated genotypes. c, As in b but Δder1 cells were transformed with low-copy number plasmids encoding mutants of Der1. d, Cycloheximide decay decay assay to determine turnover of Der1-Myc and Der1 in Δusa1 cells. The integral ER-membrane protein Sec61 served as loading control. e, Plasmid-encoded HA-tagged Der1 was expressed with endogenous Der1 in cells containing or lacking Usa1. Membranes of the total extract were solubilised with Digitonin and Der1-HA was precipitated with anti-HA antibodies followed by SDS-PAGE and immunoblotting.

Supplementary Figure 2 Characterisation of the dislocation deficient Der1 transmembrane mutants.

a, Wt and Δder1 cells were transformed with high-copy plasmids encoding HRD1 and HRD3 (pJU293) or HRD1, HRD3 and DER1 (pJU294). The turnover of CPY* was determined by radioactive pulse chase analysis and the results quantified using a PhosphoImager. b, Pulse chase experiment to analyse the effect of the Der1 transmembrane mutants on the degradation of PrA* (left panel) and 6xMyc-Hmg2 (right panel). Error bars represent the standard deviation of three independent experiments. c, Cycloheximide decay assay to monitor the stability of the Der1 transmembrane mutants. The asterisk denotes a loss of cell material during the sample preparation. d, Digitonin-solubilised lysates from cells expressing Usa1–Myc and the indicated Der1 variants were subjected to immunoprecipitation with anti-Myc antibodies (left panel). Vice versa cells expressing the indicated variants of Der1-Myc were lysed and tested for interaction to different components of the HRD-ligase by immunoprecipitation with anti-Myc antibodies (right panel). The bound proteins were analysed by SDS-PAGE and immunoblotting using specific antibodies. e, Cells expressing Der1-Myc were transformed with low-copy number plasmids encoding either Der1 or Der1 transmembrane mutants were lysed in Digitonin buffer and subjected to precipitation with anti-Myc antibodies.

Supplementary Figure 3 The pBpa-labelled Der1 variants are properly integrated into the HRD-ligase.

a, Der1-Myc labelled at positions in the first (W19) and second (S70) transmembrane domain as well as in the first luminal loop (G38, Y42, L46, K50) (derived from pMM075) were expressed in Δder1 Ubc7 C/S CPY*-HA cells to investigate crosslinking to Yos9. b, Efficiency of the CPY*-HA crosslinking to different positions in Der1-Myc. Photoreactive probes were introduced at the indicated positions of Der1-Myc (derived from pMM075) and the crosslinking experiment was performed as described (see Methods). Crosslinked CPY*-HA and precipitated pBpa-labelled Der1-Myc were detected by fluorescently labelled secondary antibodies using the Odyssey near-infrared scanner (Li-Cor) and quantified by Odyssey Imaging System Version 3.0. The amount of the CPY*-HA crosslinking at position G38 was set to 100%. The efficiency of the CPY*-HA crosslinking at other positions was calculated in relation to position G38 and normalised by the corresponding precipitated pBpa-labelled Der1-Myc variant. The asterisk denotes a cross-reactivity of the anti-Myc antibody. c, Pulse chase assay to analyse the activity of pBpa-modified Der1 variants in the degradation of CPY*. The selected Der1 constructs (derived from pMM063) form prominent crosslinks with different components of the HRD ligase as well as CPY*-HA and were expressed on high-copy plasmids in Δder1 cells. As a control unlabelled Der1 was expressed on a low-copy (wt) and high-copy plasmid (Der1 OE), respectively.d, Δder1 Ubc7C/S CPY*-HA cells expressing either various pBpa-labelled Der1-Myc constructs or unlabelled Der1-Myc were lysed in Digitonin containing buffer and subjected to immunoprecipitation with anti-Myc antibodies. Interaction partners of Der1-Myc were analysed by SDS-PAGE and immunoblotting. The asterisk denotes a cross-reactivity of the anti-Hrd1 antibody in the total lysate.

Supplementary Figure 4 Der1 is in close proximity to dislocated CPY*.

a, Photoreactive probes were placed at the indicated positions in Der1-Myc. The constructs were expressed in Δder1 Ubc7C/S CPY*-HA cells either containing or lacking Usa1 and exposed to UV light. The samples were then lysed and subjected to immunoprecipitation as described in Fig. 3. b, Der1-HA expressed from high-copy plasmid pMM079 was transformed into Δder1 Ubc7C/S cells either containing or lacking Usa1. Der1-Myc labelled with pBpa at position G38 (derived from pMM075) was co-expressed where indicated. Cells were lysed in Digitonin containing buffer and Der1-Myc was immunoprecipitated with anti-Myc antibodies. Interacting Der1-HA was detected by immunoblotting. c, Δder1 Ubc7C/S cells were transformed with a low-copy plasmid encoding Der1-HA. Microsomes of these cells were solubilised with NP40 and Der1-HA was precipitated with anti-HA antibodies. The catalytically inactive Ubc7 mutant (Ubc7C/S) was used to adjust the substrate levels in the individual strains. d, Der1-Myc constructs with photoreactive probes placed at positions which reveal prominent crosslinks with Hrd1 were expressed either in Δder1CPY*-HA cells (wt) or in Δder1CPY*-HA Ubc7C/S cells. The photocrosslinking was performed as described. e, As in d but the Der1-Myc constructs contained photoreactive probes at positions, which formed crosslinks with Usa1. f, Determination of the unfolded protein response (UPR) in strains used for the crosslinking experiments by β-galactosidase activity assay. The indicated yeast strains were transformed with the pUPRE-lacZ plasmid and the activity of β-galactosidase was measured as described (see Methods). Where indicated cells were treated with 4 mM Dithiotriol (DTT) for 1 hour before β-galactosidase measurement to fully induce the UPR. Error bars and mean values of three independent experiments are shown. g, Der1-Myc variants labelled at the indicated positions were expressed in Δpep4 Ubc7C/S cells containing plasmid-encoded PrA*-HA. The crosslinking experiment was performed as in a.

Supplementary Figure 5 The pBpa-labelled Der1RN-Myc transmembrane mutant is properly assembled with the HRD-ligase but displays alterations in the crosslinking to its interaction partners.

a, Δder1 Ubc7C/S CPY*-HA cells were transformed with high-copy plasmids encoding either pBpa-modified Der1-Myc (derived from pMM075), Der1RN-Myc (derived from pMM074) or unlabelled Der1-Myc (pMM075). Digitonin-solubilised membranes of the total extract were subjected to immunoprecipitation with anti-Myc antibodies (left and right panel). b, As in a but the microsomes were solubilised with NP40 before precipitation of the Der1-Myc constructs.

Supplementary Table 1 Characterisation of Der1 mutants generated by site-directed mutagenesis.
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Supplementary Table 2 Yeast strains used in this study.
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Supplementary Table 3 Plasmid constructs used in this study.
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Mehnert, M., Sommer, T. & Jarosch, E. Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat Cell Biol 16, 77–86 (2014). https://doi.org/10.1038/ncb2882

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