Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI:10.1073/pnas.2426917122

Tilen Tršelič, Nathalie Pelo, Gregoire Martin de Fremont, Vaishnavi S. Iyer, Elina Richardsdotter Andersson, Vijole Ottosson, David Alexander Frei, Elisa Baas, William A. Nyberg, Guðný Ella Thorlacius, Lara Mentlein, Sanjaykumar V. Boddul, Ioana Sandu, Diego Velasquez Pulgarin, Ákos Végvári, Carmen Gerlach, Fredrik Wermeling, Maria Sunnerhagen, Björn Wallner, Alexander Espinosa, Marie Wahren-Herlenius

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引用次数: 0

Abstract

Genetic association links disordered autoimmunity 1 (DIORA1) to numerous autoimmune rheumatic diseases, including systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, polymyositis, and systemic sclerosis. However, its cellular function has remained unknown. Here, we identify the Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinases (MRCK kinases) family of serine/threonine kinases—key regulators of actomyosin contractility and cell motility—as direct interactors of DIORA1. Through interaction mapping, we show that DIORA1 binds three distinct modules of MRCK kinases, including the conserved kinase inhibitory motif, C1-PH, and citron homology domains. DIORA1 knockdown in human cells altered cellular phosphorylation patterns and reduced phosphorylation of known MRCK targets. RNA-sequencing and proteomic analyses revealed upregulation of epithelial–mesenchymal transition genes and proteins, and functional analyses confirmed increased cell invasion, following knockdown of DIORA1. Together, these findings identify the autoimmunity-associated DIORA1 protein as an interactor of MRCK kinases and a regulator of cell motility.

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自身免疫相关的DIORA1结合丝氨酸/苏氨酸激酶MRCK家族并控制细胞运动

遗传关联将自身免疫失调1 （DIORA1）与许多自身免疫性风湿性疾病联系起来，包括系统性红斑狼疮、Sjögren病、类风湿性关节炎、多发性肌炎和系统性硬化症。然而，其细胞功能尚不清楚。在这里，我们发现肌强直性营养不良激酶相关cdc42结合激酶（MRCK激酶）家族的丝氨酸/苏氨酸激酶是肌动球蛋白收缩性和细胞运动性的关键调节因子，是DIORA1的直接相互作用物。通过相互作用图谱，我们发现DIORA1结合了MRCK激酶的三个不同模块，包括保守的激酶抑制基序、C1-PH和香橼同源结构域。人类细胞中DIORA1的敲低改变了细胞磷酸化模式并降低了已知MRCK靶点的磷酸化。rna测序和蛋白质组学分析显示，上皮-间质过渡基因和蛋白上调，功能分析证实，在DIORA1基因敲低后，细胞侵袭增加。总之，这些发现确定了自身免疫相关的DIORA1蛋白是MRCK激酶的相互作用因子和细胞运动的调节剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.