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Two novel chaperone-like proteins involved in ER quality control mechanism

两种新型伴侣蛋白参与 ER 质量控制机制

基本信息

批准号：
13308042
负责人：
NAGATA Kazuhiro
金额：
$ 33.95万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13308042/
关键词：
Molecular Chaperone Quality control of proteins ER associated degradation EDEM ER mannosidase HSP47 collagen

项目摘要

We found and cloned the gene of a novel stress protein HSP47 which resides in the endoplasmic reticulum (ER) acting as a collagen-specific molecular chaperone in the pathway of collagen biosynthesis, processing and secretion. HSP47 specifically and transiently binds to various types of collagen in the ER. We already succeeded in making knockout mice lacking hsp47 gene, which result in causing the embryonic lethality at 10.5 dpc in hsp47-/-homozygotic mice. In these homozygotic mice, the maturation of type I and type IV collagens was abnormal and the formation of collagen fibrils and basement membranes was impaired suggesting that HSP47 is essential molecular chaperone for collagen.We are also working on ER quality control mechanism, especially on mouse EDEM protein that we have cloned. It is known that misfolded or abnormal proteins accumulated in the ER are retrotranslocated to the cytosol for degradation, and EDEM is expected to play an important role in this process. EDEM recognize only misfolded proteins as substrates in collaboration with calnexin, a molecular chaperone in the ER, and accelerate their degradation. We recently found and cloned the functional homologues of EDEM, soluble EDEM and EDEM3, and now analyzing their functions in ER associated degradation.

我们发现并克隆了一种新的应激蛋白HSP47基因，该蛋白位于内质网（ER）中，在胶原的生物合成、加工和分泌途径中作为胶原特异性分子伴侣。在内质网中，HSP47特异且短暂地与各种类型的胶原蛋白结合。我们已经成功地制造了缺乏hsp47基因的敲除小鼠，导致hsp47-/-纯合子小鼠的胚胎死亡率为10.5 dpc。在这些纯合子小鼠中，I型和IV型胶原成熟异常，胶原原纤维和基底膜的形成受损，表明HSP47是胶原必不可少的分子伴侣。我们也在研究内质网的质量控制机制，特别是我们克隆的小鼠EDEM蛋白。众所周知，内质网中积累的错误折叠或异常蛋白会逆转录到细胞质中进行降解，EDEM有望在这一过程中发挥重要作用。EDEM只识别错误折叠的蛋白质作为底物，与内质网中的分子伴侣钙连联蛋白合作，并加速其降解。我们最近发现并克隆了EDEM、可溶性EDEM和EDEM3的功能同源物，目前正在分析它们在内质网相关降解中的功能。