Molecular mechanism of ER-related degradation

这一时期我们在内质网错误折叠蛋白的质量控制机制方面有了一些重要的新发现。首先，我们确定EDEM是识别通过er相关降解（ERAD）系统降解的错误折叠蛋白质的新成分：EDEM识别错误折叠蛋白质上的甘露糖8形式的n -聚糖，并促进ERAD。另一方面，我们也明确了胞质伴侣蛋白CCT抑制Huntingtin等多谷氨酰胺重复蛋白聚集形成的机制。CCT抑制polyQ蛋白的低聚物形成，从而抑制聚集。我们还确定了CCT在含有生产性折叠蛋白的β -薄片上可以识别的序列。Hsp47是我们在1986年发现的一种胶原特异性分子伴侣，最近发现它对分泌到细胞外基质中的胶原形成纤维至关重要。没有Hsp47，分泌的胶原不能形成厚的胶原束，提示Hsp47是包括肝硬化在内的各种纤维化疾病的有希望的治疗靶点。

We have got several important new findings during this period on the quality control mechanism of misfolded proteins in the endoplasmic reticulum. First, we identified EDEM as a novel component for the recognition of misfolded proteins that are to be degraded through ER-associated degradation (ERAD) system: EDEM recognizes mannose 8 form of N-glycans on the misfolded proteins and facilitates the ERAD. On the other hand, we also figured out the mechanism on the inhibition of aggregate formation of poly-glutamine repeat proteins such as Huntingtin by cytosolic chaperonin CCT. CCT inhibited the oligomer formation of polyQ proteins resulting in inhibiting the aggregation. We also identified the sequence that can be recognized by CCT on the beta-sheet containing proteins for the productive folding. Hsp47, a collagen-specific molecular chaperone that we found in 1986, was newly found to be essential for fibril formation by collagen secreted into the extracellular matrix. Without Hsp47, secreted collagen failed to make thick collagen bundles, which suggested Hsp47 is a promising therapeutic target for various fibrotic diseases including liver cirrhosis.