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，我们有几个重要的新发现，涉及内质网中错误折叠蛋白的质量控制机制。首先，我们将EDEM确定为识别错误折叠蛋白的新成分，这些成分将通过与ER相关的降解（ERAD）系统降解：EDEM识别错误折叠蛋白上的N-聚糖形式的N-聚糖形式并促进ERAD。另一方面，我们还发现了抑制聚谷氨酰胺重复蛋白（例如胞质伴侣伴侣CCT）聚集的机制。 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可以在包含生产折叠的蛋白质的Beta表上识别的序列。 HSP47是我们在1986年发现的一种胶原特异性分子伴侣，新发现是胶原蛋白分泌到细胞外基质中的原纤维形成至关重要的。没有HSP47，分泌的胶原蛋白无法制成较厚的胶原蛋白束，这表明HSP47是包括肝肝硬化在内的各种纤维化疾病的有前途的治疗靶标。

项目成果

EDEM cooperates with calnexin in the ER associated degradation of unfolded proteins

EDEM 与钙联蛋白合作参与 ER 相关的未折叠蛋白降解

• 发表时间: 2003
• 作者: K. Nagata;K. Nagata;K. Nagata
• 通讯作者: K. Nagata

K.YASUDA: "The Kruppel-like factor Zf9 and proteins in the Sp1 family regulate the expression of HSP47, a collagen-specific molecular chaperone"J Biol Chem.. 277(47). 44613-44622 (2002)

K.YASUDA：“Kruppel 样因子 Zf9 和 Sp1 家族中的蛋白质调节 HSP47（一种胶原蛋白特异性分子伴侣）的表达”J Biol Chem.. 277(47)。

Y.ODA: "EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin"Science. 299(5611). 1394-1397 (2003)

Y.ODA：“EDEM 作为从钙联蛋白释放的末端错误折叠糖蛋白的受体”科学。

The maintenance of the endoplasmic reticulum network is regulated by p47, a cofactor of p97, through phosphorvlation by cdc2 kinase.

内质网网络的维持由 p47（p97 的辅助因子）通过 cdc2 激酶的磷酸化来调节。

• 发表时间: 2005
• 期刊: Genes Cells. 10(4)
• 作者: Ito;K.;Shimohata;N.;Nagamori;S.;Kaback;H. R.;Sakoh;M.;Chiba;S.;Mori;H. Akiyama;Y.;F. Kano
• 通讯作者: F. Kano

Quality Control Mechanism of the Unfolded Proteins in ER.

ER 中未折叠蛋白的质量控制机制。

• 发表时间: 2003
• 作者: K. Nagata