Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress

Hyperhomocysteinemia, a risk factor for vascular disease, injures endotheli al cells through undefined mechanisms. We previously identified several hom ocysteine-responsive genes in cultured human vascular endothelial cells, in cluding the endoplasmic reticulum (ER)-resident molecular chaperone GRP78/B iP. Here, we demonstrate that homocysteine induces the ER stress response a nd leads to the expression of a novel protein, Herp, containing a ubiquitin -like domain at the N terminus. mRNA expression of Herp was strongly upregu lated by inducers of ER stress, including mercaptoethanol, tunicamycin, A23 187, and thapsigargin. The ER stress-dependent induction of Herp was also o bserved at the protein level. Immunochemical analyses using Herp-specific a ntibodies indicated that Herp is a 54-kDa, membrane-associated ER protein. Herp is the first integral membrane protein regulated by the ER stress resp onse pathway. Both the N and C termini face the cytoplasmic side of the ER; this membrane topology makes it unlikely that Herp acts as a molecular cha perone for proteins in the ER, in contrast to GRP78 and other ER stress-res ponsive proteins. Herp may, therefore, play an unknown role in the cellular survival response to stress.