Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD

Julia Leitman, Marina Shenkman, Yana Gofmanb, Navit Ogen Shtern, Nir Ben-Tal, Linda M. Hendershot, Gerardo Z. Lederkremer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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 2a 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.

Original languageEnglish
Pages (from-to)1050-1060
Number of pages11
JournalMolecular Biology of the Cell
Issue number7
StatePublished - 1 Apr 2014


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