低複雑性ドメインによる相分離は,ストレス粒子の組み立てを促進し,病理的フィブリル化を誘発する

Amandine Molliex¹, Jamshid Temirov², Jihun Lee³

¹Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

|September 26, 2015

まとめ

神経退行性疾患に関わる持続的なストレス粒子は病的なタンパク質インクルージョンを形成する可能性がありますこの研究では,RNA結合タンパク質 hnRNPA1 が,液体-液体相分離によるストレス粒子の形成を駆動し,粒子の持続性と疾患の病理性を関連付けていることが示されています.

科学分野:

細胞生物学
神経科学
生物化学

背景:

ストレス粒子は動的RNA-タンパク質複合体で ALSのような神経退行性疾患に関与しています
ストレス粒子の機能障害と持続的な粒子は,病的なタンパク質含有と関連しています.

研究の目的:

ストレス粒子の形成におけるRNA結合タンパク質 hnRNPA1 の役割を調査する.
hnRNPA1が液体-液体相分離 (LLPS) とその後のタンパク質集積に寄与するメカニズムを解明する.

主な方法:

hnRNPA1の低複雑性領域 (LCD) とRNA認識モチーフ (RRMs) を研究した.
hnRNPA1がLLPSを in vitroで受けられる能力を調査した.
タンパク質フィブリル化に対するLLPSの影響を評価した.

主要な成果:

hnRNPA1のLCDはLLPSを媒介し,液滴を形成するのに十分である.
RRMは,RNAの存在でLLPSの調節に寄与する.
タンパク質に富んだドロップルは線維を強めるが,そのためにはLLPSは必要ない.

結論:

hnRNPA1媒介のLLPSは,ストレス粒子の組立と液体の性質に寄与する.
これは,ALSのような疾患における,持続的なストレス粒子の間のメカニズム的関連性を示しています.

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