研究者らが変性疾患治療の新しいアプローチを明らかにする(Researchers reveal a new approach for treating degenerative diseases)

2024-05-01

2024-04-30 カリフォルニア大学サンタバーバラ校(UCSB)

カリフォルニア大学サンタバーバラ校の研究により、ZIP7という遺伝子がコードするタンパク質が、細胞の「ごみ処理機」であるプロテアソームと連携して誤って折りたたまれたタンパク質を分解し、細胞の動きを改善することが明らかになりました。この発見は、レチニティス・ピグメントーサなどの治療不可能な病気の新たな治療法につながる可能性があります。ZIP7が高発現することで、誤折り畳みタンパク質の蓄積が防がれ、細胞が正常に機能することが示されました。この研究は基礎研究から始まり、病気の治療法につながる可能性を見出しました。

<関連情報>

Zn2+輸送体ZIP7は小胞体関連タンパク質の分解を促進し、ショウジョウバエの神経変性を防ぐ The Zn2+ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila

Xiaoran Guo, Morgan Mutch, Alba Yurani Torres, Maddalena Nano, Nishi Rauth, Jacob Harwood, Drew McDonald, Zijing Chen, Craig Montell, Wei Dai, Denise J. Montell
Developmental Cell Published: April 25, 2024
DOI:https://doi.org/10.1016/j.devcel.2024.04.003

Highlights

•The ER-localized Zn²⁺ transporter ZIP7 promotes ER-associated degradation (ERAD)

•ZIP7 provides rate-limiting Zn²⁺ to degrade proteins that misfold in the ER

•ZIP7 enhances protein deubiquitination by the Zn²⁺ metalloproteinase Rpn11

•ZIP7 overexpression prevents blindness in a Drosophila model of neurodegeneration

Summary

Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn²⁺ transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn²⁺ transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn²⁺ metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn²⁺ are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn²⁺ transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.