derlin-1 deficiency is embryonic lethal, derlin-3 deficiency appears normal, and herp deficiency is intolerant to glucose load and ischemia in micederlin-1缺乏是胚胎致死,derlin-3不足出现正常和爬虫缺乏是不能容忍在小鼠葡萄糖负荷和缺血.pdfVIP

Derlin-1 Deficiency Is Embryonic Lethal, Derlin-3 Deficiency Appears Normal, and Herp Deficiency Is Intolerant to Glucose Load and Ischemia in Mice 1 2 3 1 1 1 Yuka Eura , Hiroji Yanamoto , Yuji Arai , Tomohiko Okuda , Toshiyuki Miyata , Koichi Kokame * 1 Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan, 2 Laboratory of Neurology and Neurosurgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan, 3 Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan Abstract Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes a cellular condition called ER stress. To overcome ER stress, unfolded proteins are eliminated by an ER-associated degradation (ERAD) system. To explore the physiological requirements for ERAD-related membrane proteins in mammals, we generated Derlin-1–, Derlin-3–, and Herp-deficient mice by gene targeting. Complete loss of Derlin-1 caused embryonic lethality at around E7–E8 (early somite stages). In contrast, Derlin-3– and Herp-deficient mice were born alive with the expected Mendelian frequency, and were superficially indistinguishable from wild-type mice. However, in the Derlin-3– and Herp-deficient mouse organs, the expression levels of ERAD-related proteins were affected under both normal and ER stress conditions; specific effects differed among the organs. Degradation of ERAD substrates was reduced in the Herp-deficient liver, and Herp-deficient mice exhibited impaired glucose tolerance and vulnerability to brain ischemic injury, both of which are known to be implicated