2025-09-30 カロリンスカ研究所(KI)
<関連情報>
- https://news.ki.se/gene-linked-to-rheumatic-disease-controls-cell-movement
- https://www.pnas.org/doi/10.1073/pnas.2426917122
自己免疫関連DIORA1はセリン/スレオニンキナーゼのMRCKファミリーに結合し、細胞運動を制御する Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility
Tilen Tršelič, Nathalie Pelo, Gregoire Martin de Fremont, +17 , and Marie Wahren-Herlenius
Proceedings of the National Academy of Sciences Published:October 3, 2025
DOI:https://doi.org/10.1073/pnas.2426917122
Significance
Disordered autoimmunity 1 (DIORA1) has been genetically linked to multiple autoimmune rheumatic diseases, but its cellular function has remained unknown. In this study, we identify DIORA1 as a direct interactor of Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinases (MRCK kinases), which are key effectors in the Rho GTPase signaling pathway. DIORA1 knockdown reduced phosphorylation of established MRCK targets and induced transcriptomic and proteomic changes associated with epithelial–mesenchymal transition, alongside enhanced cell invasion. These findings reveal a role for DIORA1 as an interactor of a small but specific group of kinases and a regulator of cell motility. The data provide a foundation for future studies exploring the importance of DIORA1 in autoimmune pathogenicity and other motility-driven biological processes, such as cancer metastasis.
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.
