2024年3月29日，美国贝勒医学院André Catic课题组在《自然—细胞生物学》杂志发表论文发现，亲环蛋白A支持内在无序蛋白的翻译并影响造血干细胞的老化。

研究人员发现，肽基脯氨酰异构酶A（PPIA或亲环蛋白A）是造血干细胞和祖细胞中的主要伴侣。PPIA的消耗会加速干细胞老化。研究人员发现，具有内在无序区（IDR）的蛋白质是PPIA的常见底物。IDR促进了与其他蛋白质或核酸的相互作用，并能引发液-液相分离。超过20%的PPIA底物参与了超分子无膜细胞器的形成。

PPIA影响应激颗粒（PABPC1）、P-体（DDX6）和核小体（NPM1）的调节因子，从而促进相分离，增强细胞的抗应激能力。造血干细胞的衰老与PPIA表达的转录后减少和富含IDR蛋白的翻译减少有关。研究人员将伴侣PPIA与内在无序蛋白的合成联系起来，这表明受损的蛋白质相互作用网络和大分子凝聚，可能是造血干细胞老化的潜在决定因素。

附：英文原文

Title: Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing

Author: Maneix, Laure, Iakova, Polina, Lee, Charles G., Moree, Shannon E., Lu, Xuan, Datar, Gandhar K., Hill, Cedric T., Spooner, Eric, King, Jordon C. K., Sykes, David B., Saez, Borja, Di Stefano, Bruno, Chen, Xi, Krause, Daniela S., Sahin, Ergun, Tsai, Francis T. F., Goodell, Margaret A., Berk, Bradford C., Scadden, David T., Catic, Andr

Issue&Volume: 2024-03-29

Abstract: Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid–liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.

DOI: 10.1038/s41556-024-01387-x

Source: https://www.nature.com/articles/s41556-024-01387-x