Molecular mechanism of ER-related degradation

ER相关降解的分子机制

• 批准号: 14037230
• 负责人: NAGATA Kazuhiro
• 金额: $ 60.8万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14037230/
• 关键词: Molecular Chaperone; Quality control; ER associated degradation; EDEM; 小胞体関連分野; 分子シヤペロン

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.

在此期间，我们在内质网中错误折叠蛋白质的质量控制机制方面有了一些重要的新发现。首先，我们将EDEM确定为识别通过ER相关降解（ERAD）系统降解的错误折叠蛋白质的新型成分：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，我们也阐明了胞质伴侣蛋白CCT抑制亨廷顿蛋白等多聚谷氨酰胺重复序列蛋白聚集体形成的机制。CCT抑制polyQ蛋白的寡聚体形成，从而抑制聚集。我们还鉴定了可被CCT识别的含有β折叠的蛋白质上的序列，用于生产性折叠。Hsp 47是我们在1986年发现的一种胶原特异性分子伴侣，是新近发现的一种胶原分泌到细胞外基质中形成原纤维所必需的分子伴侣。没有Hsp 47，分泌的胶原不能形成厚的胶原束，这表明Hsp 47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。

项目成果

The endoplasmic reticulum stress response is stimulated through the continuous activation of transcript ion factors ATF6 and x. BP1 in lns2^<+/Akita>pancreatic beta cells.

通过转录离子因子 ATF6 和 x 的持续激活来刺激内质网应激反应。

• 发表时间: 2004
• 期刊: Genes Cells 9
• 作者: J. Nozaki

Accumulation of type IV collagen in dilated endoplasmic reticulum leads to apoptosis HSP47-knockout mouse embryos through the induction of CHOP

IV型胶原在扩张内质网中的积累通过诱导CHOP导致HSP47敲除小鼠胚胎凋亡

• 发表时间: 2004
• 期刊: J. Cell. Sci. 117
• 作者: Akio Kato;Shigeru Utsumi;Toshihiko Utsumi;Yasushi Kawata;Yuriko Yamagata;Akihiko Yamagishi;Masaaki Yoshikawa;Y. Matsuoka;河田康志(加藤昭夫編集);T. Marutani
• 通讯作者: T. Marutani

S.YOKOTA: "Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease."Biochem Biophys Res Commun.. 303. 413-418 (2003)

S.YOKOTA：“混合结缔组织病患者血清中 HSP47 抗原和 HSP47 自身抗体的患病率。”Biochem Biophys Res Commun.. 303. 413-418 (2003)

K.SATO: "Type XXVI collagen, a new member of the collagen family, is speclfically expressed in the testis and ovary"J Biol Chem.. 277(40). 37678-37684 (2002)

K.SATO：“XXVI 型胶原蛋白是胶原蛋白家族的新成员，在睾丸和卵巢中特异性表达”J Biol Chem.. 277(40)。

Substrate recognition by HSP47, a colagen-specific molecular chaperone, as amember of serpin superfamily.

HSP47（一种胶原蛋白特异性分子伴侣）对底物的识别，是丝氨酸蛋白酶抑制剂超家族的成员。

• 发表时间: 2005
• 作者: K. Nagata