Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD.
A functional unfolded protein response (UPR) is essential for endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded secretory proteins, reflecting the fact that some level of UPR activation must exist under normal physiological conditions. A coordinator of the UPR and ERAD processes has long been sought. We previously showed that the PKR-like, ER-localized eukaryotic translation initiation factor 2α kinase branch of the UPR is required for the recruitment of misfolded proteins and the ubiquitin ligase HRD1 to the ER-derived quality control compartment (ERQC), a staging ground for ERAD. Here we show that homocysteine-induced ER protein (Herp), a protein highly upregulated by this UPR branch, is responsible for this compartmentalization. Herp localizes to the ERQC, and our results suggest that it recruits HRD1, which targets to ERAD the substrate presented by the OS-9 lectin at the ERQC. Predicted overall structural similarity of Herp to the ubiquitin-proteasome shuttle hHR23, but including a transmembrane hairpin, suggests that Herp may function as a hub for membrane association of ERAD machinery components, a key organizer of the ERAD complex.
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Julia
J
Leitman
Marina
M
Shenkman
Yana
Y
Gofman
Navit Ogen
NO
Shtern
Nir
N
Ben-Tal
Linda M
LM
Hendershot
Gerardo Z
GZ
Lederkremer
D000818:Animals; D002451:Cell Compartmentation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D021381:Protein Transport; D059748:Proteolysis; D013379:Substrate Specificity; D051742:Transcription Factor CHOP / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D056811:Unfolded Protein Response
D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; C415829:Herpud1 protein, mouse; D037102:Lectins; D008565:Membrane Proteins; D050505:Mutant Proteins; D051742:Transcription Factor CHOP; C086985:RAD23A protein, human; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D045643:DNA Repair Enzymes