Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress.
Hyperhomocysteinemia, a risk factor for vascular disease, injures endothelial cells through undefined mechanisms. We previously identified several homocysteine-responsive genes in cultured human vascular endothelial cells, including the endoplasmic reticulum (ER)-resident molecular chaperone GRP78/BiP. Here, we demonstrate that homocysteine induces the ER stress response and leads to the expression of a novel protein, Herp, containing a ubiquitin-like domain at the N terminus. mRNA expression of Herp was strongly up-regulated by inducers of ER stress, including mercaptoethanol, tunicamycin, A23187, and thapsigargin. The ER stress-dependent induction of Herp was also observed at the protein level. Immunochemical analyses using Herp-specific antibodies indicated that Herp is a 54-kDa, membrane-associated ER protein. Herp is the first integral membrane protein regulated by the ER stress response 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 chaperone for proteins in the ER, in contrast to GRP78 and other ER stress-responsive proteins. Herp may, therefore, play an unknown role in the cellular survival response to stress.
Kokame
K
K
National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. kame@ri.ncvc.go.jp
Agarwala
K L
KL
Kato
H
H
Miyata
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology / Q000648:ultrastructure; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D008623:Mercaptoethanol / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019284:Thapsigargin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology; D014452:Ubiquitins / Q000737:chemistry*; D014471:Umbilical Veins
D000091342:Endoplasmic Reticulum Chaperone BiP; C485932:HERPUD1 protein, human; C000717247:HSPA5 protein, human; C415829:Herpud1 protein, mouse; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014452:Ubiquitins; D014415:Tunicamycin; D000001:Calcimycin; D008623:Mercaptoethanol; D019284:Thapsigargin