{"title":"ATF6α 和 ATF6β 双基因敲除对细胞功能的部分限制和对未折叠蛋白反应途径的补偿调节","authors":"Ryoko Akai , Hisayo Hamashima , Michiko Saito , Kenji Kohno , Takao Iwawaki","doi":"10.1016/j.cstres.2023.11.002","DOIUrl":null,"url":null,"abstract":"<div><p>Mammalian cells have three types of endoplasmic reticulum (ER) stress-sensing molecules: ATF6, IRE1, and PERK. Among these, ATF6 is unique in that it is processed in an ER-stress-specific manner and functions as a transcription factor for the activation of anti-ER stress genes (such as BiP). ATF6 is known to have two homologues, ATF6α and ATF6β, and a greater understanding of their functions has been achieved through analyses using cultured cells. Physiological functions are also gradually being investigated in mice lacking ATF6α or ATF6β. However, little is known about the effects on mouse organisms of the deletion of both the ATF6α and ATF6β genes, since such double-knockout (DKO) mice suffer embryonic lethality at an early developmental stage. In this study, we generated and analyzed ATF6 DKO mice in which embryonic lethality was evaded by using Cre/loxP technology. Pancreatic β cell-specific ATF6 DKO mice were born normally and lived without dysregulation of blood-glucose levels but had a reduced tolerance to glucose. Islets isolated from ATF6 DKO mice also showed low production and secretion of insulin and mild enhancement of IRE1 and PERK activity. We further examined the developmental abnormalities of systemic ATF6 DKO mice. The phenotypes of ATF6α<sup>−/−</sup>; ATF6β<sup>−/−</sup> mice were similar to those previously reported, but ATF6α<sup>+/−</sup>; ATF6β<sup>−/−</sup> and ATF6α<sup>−/−</sup>; ATF6β<sup>+/−</sup> mice showed embryonic lethality at middle developmental stages, unlike those reported. Analysis of embryonic fibroblasts derived from these mice revealed that ATF6α and ATF6β have a gene-dose-dependent functional redundancy and display distinct differences in their ability to induce BiP expression. (250 words)</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 1","pages":"Pages 34-48"},"PeriodicalIF":3.3000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814523022423/pdfft?md5=0a26f91ad555e96cdde3e0902dd50c3e&pid=1-s2.0-S1355814523022423-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Partial limitation of cellular functions and compensatory modulation of unfolded protein response pathways caused by double-knockout of ATF6α and ATF6β\",\"authors\":\"Ryoko Akai , Hisayo Hamashima , Michiko Saito , Kenji Kohno , Takao Iwawaki\",\"doi\":\"10.1016/j.cstres.2023.11.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Mammalian cells have three types of endoplasmic reticulum (ER) stress-sensing molecules: ATF6, IRE1, and PERK. Among these, ATF6 is unique in that it is processed in an ER-stress-specific manner and functions as a transcription factor for the activation of anti-ER stress genes (such as BiP). ATF6 is known to have two homologues, ATF6α and ATF6β, and a greater understanding of their functions has been achieved through analyses using cultured cells. Physiological functions are also gradually being investigated in mice lacking ATF6α or ATF6β. However, little is known about the effects on mouse organisms of the deletion of both the ATF6α and ATF6β genes, since such double-knockout (DKO) mice suffer embryonic lethality at an early developmental stage. In this study, we generated and analyzed ATF6 DKO mice in which embryonic lethality was evaded by using Cre/loxP technology. Pancreatic β cell-specific ATF6 DKO mice were born normally and lived without dysregulation of blood-glucose levels but had a reduced tolerance to glucose. Islets isolated from ATF6 DKO mice also showed low production and secretion of insulin and mild enhancement of IRE1 and PERK activity. We further examined the developmental abnormalities of systemic ATF6 DKO mice. The phenotypes of ATF6α<sup>−/−</sup>; ATF6β<sup>−/−</sup> mice were similar to those previously reported, but ATF6α<sup>+/−</sup>; ATF6β<sup>−/−</sup> and ATF6α<sup>−/−</sup>; ATF6β<sup>+/−</sup> mice showed embryonic lethality at middle developmental stages, unlike those reported. Analysis of embryonic fibroblasts derived from these mice revealed that ATF6α and ATF6β have a gene-dose-dependent functional redundancy and display distinct differences in their ability to induce BiP expression. (250 words)</p></div>\",\"PeriodicalId\":9684,\"journal\":{\"name\":\"Cell Stress & Chaperones\",\"volume\":\"29 1\",\"pages\":\"Pages 34-48\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1355814523022423/pdfft?md5=0a26f91ad555e96cdde3e0902dd50c3e&pid=1-s2.0-S1355814523022423-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Stress & Chaperones\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1355814523022423\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Stress & Chaperones","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1355814523022423","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Partial limitation of cellular functions and compensatory modulation of unfolded protein response pathways caused by double-knockout of ATF6α and ATF6β
Mammalian cells have three types of endoplasmic reticulum (ER) stress-sensing molecules: ATF6, IRE1, and PERK. Among these, ATF6 is unique in that it is processed in an ER-stress-specific manner and functions as a transcription factor for the activation of anti-ER stress genes (such as BiP). ATF6 is known to have two homologues, ATF6α and ATF6β, and a greater understanding of their functions has been achieved through analyses using cultured cells. Physiological functions are also gradually being investigated in mice lacking ATF6α or ATF6β. However, little is known about the effects on mouse organisms of the deletion of both the ATF6α and ATF6β genes, since such double-knockout (DKO) mice suffer embryonic lethality at an early developmental stage. In this study, we generated and analyzed ATF6 DKO mice in which embryonic lethality was evaded by using Cre/loxP technology. Pancreatic β cell-specific ATF6 DKO mice were born normally and lived without dysregulation of blood-glucose levels but had a reduced tolerance to glucose. Islets isolated from ATF6 DKO mice also showed low production and secretion of insulin and mild enhancement of IRE1 and PERK activity. We further examined the developmental abnormalities of systemic ATF6 DKO mice. The phenotypes of ATF6α−/−; ATF6β−/− mice were similar to those previously reported, but ATF6α+/−; ATF6β−/− and ATF6α−/−; ATF6β+/− mice showed embryonic lethality at middle developmental stages, unlike those reported. Analysis of embryonic fibroblasts derived from these mice revealed that ATF6α and ATF6β have a gene-dose-dependent functional redundancy and display distinct differences in their ability to induce BiP expression. (250 words)
期刊介绍:
Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.