SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER.
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.
Mueller
Britta
B
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Lilley
Brendan N
BN
Ploegh
Hidde L
HL
D000818:Animals; D003587:Cytomegalovirus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D019673:Genes, T-Cell Receptor alpha / Q000502:physiology; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D025801:Ubiquitin / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
C487709:DERL1 protein, human; C513305:DERL2 protein, human; C104622:HRD3 protein, S cerevisiae; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C117384:SEL1L protein, human; D029701:Saccharomyces cerevisiae Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D025801:Ubiquitin; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C034241:ribophorin; D046988:Proteasome Endopeptidase Complex