Protein quality control in the endoplasmic reticulum (ER) involves recognition of misfolded proteins and dislocation from the ER lumen into the cytosol, followed by proteasomal degradation. Viruses have co-opted this pathway to destroy proteins that are crucial for host defense. Examination of dislocation of class I major histocompatibility complex (MHC) heavy chains (HCs) catalyzed by the human cytomegalovirus (HCMV) immunoevasin US11 uncovered a conserved complex of the mammalian dislocation machinery. We analyze the contributions of a novel complex member, SEL1L, mammalian homologue of yHrd3p, to the dislocation process. Perturbation of SEL1L function discriminates between the dislocation pathways used by US11 and US2, which is a second HCMV protein that catalyzes dislocation of class I MHC HCs. Furthermore, reduction of the level of SEL1L by small hairpin RNA (shRNA) inhibits the degradation of a misfolded ribophorin fragment (RI332) independently of the presence of viral accessories. These results allow us to place SEL1L in the broader context of glycoprotein degradation, and imply the existence of multiple independent modes of extraction of misfolded substrates from the mammalian ER.
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23 October 2006
Article|
October 16 2006
SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER
Britta Mueller,
Britta Mueller
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
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Brendan N. Lilley,
Brendan N. Lilley
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
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Hidde L. Ploegh
Hidde L. Ploegh
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
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Britta Mueller
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
Brendan N. Lilley
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
Hidde L. Ploegh
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
Correspondence to Hidde L. Ploegh: [email protected]
B.N. Lilley's present address is Dept. of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138.
Abbreviations used in this paper: CPY, carboxypeptidase Y; EDEM, ER degradation-enhancing mannosidase-like; HC, heavy chain; MHC, major histocompatibility complex; NHK, null Hong Kong; PDI, protein disulfide isomerase; shRNA, small hairpin RNA; HCMV, human cytomegalovirus; RI, ribophorin; TPR, tetratricopeptide repeat.
Received:
May 31 2006
Accepted:
September 11 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 175 (2): 261–270.
Article history
Received:
May 31 2006
Accepted:
September 11 2006
Citation
Britta Mueller, Brendan N. Lilley, Hidde L. Ploegh; SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER . J Cell Biol 23 October 2006; 175 (2): 261–270. doi: https://doi.org/10.1083/jcb.200605196
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