Herp, a New Ubiquitin-like Membrane Protein Induced by Endoplasmic Reticulum Stress*
- From the National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
Abstract
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.
Footnotes
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↵* This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan, by Grants-in-Aid from the Ministry of Health and Welfare of Japan, and by Special Coordination Funds for Promoting Science and Technology (Encouragement System of Center of Excellence) from the Science and Technology Agency of Japan. .The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) and .
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↵‡ To whom corresponding should be addressed: National Cardiovascular Center Research Inst., 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Tel.: 81-6-6833-5012, Ext. 2589; Fax: 81-6-6872-8091; E-mail: kame@ri.ncvc.go.jp.
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↵§ Recipient of National Institute Post Doctoral Fellowship of Research Development Corporation of Japan. Present address: RIKEN Brain Science Inst., 2-1 Hirosawa, Saitama 351-0198, Japan.
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Published, JBC Papers in Press, August 1, 2000, DOI 10.1074/jbc.M002063200
- Abbreviations:
- HUVEC
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human umbilical vein endothelial cell
- ER
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endoplasmic reticulum
- UPR
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unfolded protein response
- SLO
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streptolysin O
- PBS
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phosphate-buffered saline
- PCR
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polymerase chain reaction
- MOPS
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4-morpholinepropanesulfonic acid
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- Received March 13, 2000.
- Revision received July 31, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
