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

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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.