Istituto Nazionale Tumori-IRCSS-Fondazione G. Pascale, 80131 Naples, Italy.
Department of Biology, University of Naples Federico II, 80126 Naples, Italy.
Genes (Basel). 2023 Sep 6;14(9):1766. doi: 10.3390/genes14091766.
The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl-prolyl cis-trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal-Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs.
亲环素家族高度保守，包含多种具有与蛋白质和 RNA 相互作用的多功能伴侣分子，促进涉及各种细胞过程的多分子复合物的动态组装。该家族的主要成员亲环素 A（CypA）具有肽脯氨酰顺反异构酶活性。这种酶促功能有助于蛋白质结构的折叠和激活，并经常作为大的多分子复合物的分子调节开关，确保适当的分子间和分子内相互作用。在这里，我们研究了 CypA 在核中的参与，它在支持异质核糖核蛋白（RNP）的组装和运输中起着关键作用。我们揭示 CypA 在核仁中富集，在核仁中与假尿嘧啶合酶 dyskerin 共定位，dyskerin 是涉及细胞 RNA 修饰和端粒稳定性的多功能 H/ACA RNP 的催化成分。我们表明 dyskerin 可以直接与 CypA 相互作用，其突变会导致 X 连锁的角化不良（X-DC）和 Hoyeraal-Hreidarsson 先天性核糖体病。这些发现，以及取代四个 dyskerin 脯氨酸已知会导致 X-DC 致病性突变的事实，使我们将该蛋白鉴定为 CypA 的靶标。这里提出的数据表明，这种伴侣可以调节 dyskerin 活性，影响所有与其相关的 RNP。
