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...
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| Veröffentlicht in: | Molecular biology of the cell 2014-04, Vol.25 (7), p.1050-1060 |
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| container_title | Molecular biology of the cell |
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| creator | Leitman, Julia Shenkman, Marina Gofman, Yana Shtern, Navit Ogen Ben-Tal, Nir Hendershot, Linda M Lederkremer, Gerardo Z |
| description | 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. |
| doi_str_mv | 10.1091/mbc.E13-06-0350 |
| format | Article |
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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. 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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.</description><subject>Animals</subject><subject>Cell Compartmentation</subject><subject>Cell Line</subject><subject>Cell Membrane - metabolism</subject><subject>DNA Repair Enzymes</subject><subject>DNA-Binding Proteins</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endoplasmic Reticulum-Associated Degradation</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Lectins - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Mutant Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Folding</subject><subject>Protein Transport</subject><subject>Proteolysis</subject><subject>Substrate Specificity</subject><subject>Transcription Factor CHOP - metabolism</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Unfolded Protein Response</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LAzEQDaJo_Th7kz16WZs0X5uLULRaoSAUPUpI86GR3c2abAX99aYfFj3NMO_Nmzc8AM4RvEJQoGGz0FcThEvISogp3AMDJLAoCa3Yfu4hFSWiI3IEjlN6hxARwvghOBoRwitC8QC8TG3sCh1CNL5VvU25bzoV-8a2var9t-p9aAvVmiJaHZd-DRTBFdP5LVrPG59cqI01RRdDb32bChdiMZmPb0_BgVN1smfbegKe7yZPN9Ny9nj_cDOelZpC2pdUK6Yct85wzBaEET7CWI3MghkCafaMncHGOqgpcpWpFK8YN1QLIZCDmOETcL3R7ZaLxhqdLUZVyy76RsUvGZSX_5HWv8nX8CmxYFxwmAUutwIxfCxt6mX-Stu6Vq0NyyQRRQgLRDjJ1OGGqmNIKVq3O4OgXIUicyjSIiwhk6tQ8sbFX3c7_m8K-AcPa4pf</recordid><startdate>201404</startdate><enddate>201404</enddate><creator>Leitman, Julia</creator><creator>Shenkman, Marina</creator><creator>Gofman, Yana</creator><creator>Shtern, Navit Ogen</creator><creator>Ben-Tal, Nir</creator><creator>Hendershot, Linda M</creator><creator>Lederkremer, Gerardo Z</creator><general>The American Society for Cell Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201404</creationdate><title>Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD</title><author>Leitman, Julia ; 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| subjects | Animals Cell Compartmentation Cell Line Cell Membrane - metabolism DNA Repair Enzymes DNA-Binding Proteins Endoplasmic Reticulum - metabolism Endoplasmic Reticulum-Associated Degradation Eukaryotic Initiation Factor-2 - metabolism Gene Knockdown Techniques Glycosylation Humans Lectins - metabolism Membrane Proteins - metabolism Mice Models, Biological Mutant Proteins - metabolism Phosphorylation Protein Folding Protein Transport Proteolysis Substrate Specificity Transcription Factor CHOP - metabolism Ubiquitin-Protein Ligases - metabolism Unfolded Protein Response |
| title | Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD |
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