Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp.
To investigate the disposal of nonglycosylated BiP substrates, we used a nonsecreted kappa LC, which exists in partially (ox1) and completely (ox2) oxidized states. The ox2 form is partially reduced in order to be degraded, and only the ox1 form is ubiquitinated and associates with both Herp and Derlin-1. Herp is in a complex with ubiquitinated proteins and with the 26S proteasome, suggesting that it plays a role in linking substrates with the proteasome. Overexpressed Herp also interacts with two other BiP substrates, but not with two calnexin substrates. Either expression of p97 or Hrd1 mutants, which are in a complex with Herp and Derlin-1, or reduction of Herp levels inhibited the degradation of the BiP substrates, whereas the latter had no effect on the degradation of the calnexin substrates. This result suggests that there is some distinction in the pathways used to dispose of these two types of ERAD substrates.
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yuki
Y
Okuda-Shimizu
Linda M
LM
Hendershot
D000818:Animals; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006031:Glycosylation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D037282:Calreticulin; D000091342:Endoplasmic Reticulum Chaperone BiP; C485932:HERPUD1 protein, human; D006360:Heat-Shock Proteins; C415829:Herpud1 protein, mouse; D007145:Immunoglobulin kappa-Chains; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D037281:Calnexin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex