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

我们发现并克隆了一种新的应激蛋白HSP47的基因，它位于内质网(ER)中，在胶原的生物合成、加工和分泌过程中扮演着胶原特异性分子伴侣的角色。HSP47可与内质网中各种类型的胶原特异性地瞬时结合。我们已经成功地制造了缺失hsp47基因的基因敲除小鼠，这导致了hsp47-/-纯合子小鼠在10.5dpc时的胚胎死亡。在这些纯合子小鼠中，I型和IV型胶原的成熟异常，胶原纤维和基底膜的形成受阻，这表明HSP47是胶原蛋白必不可少的分子伴侣。我们还在研究ER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被逆转录到胞浆中进行降解，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Calnexin合作，并加速它们的降解。我们最近发现并克隆了EDEM、可溶性EDEM和EDEM3的功能同源物，并分析了它们在内质网相关降解中的作用。

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.