Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility
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.
Authors
- Ioana Sandu (ORCID: https://orcid.org/0000-0003-4696-0683)
- Fredrik Wermeling (ORCID: https://orcid.org/0000-0001-9633-677X)
- E. J. Baas
- Björn Wallner (ORCID: https://orcid.org/0000-0002-3772-8279)
- Carmen Gerlach (ORCID: https://orcid.org/0000-0001-7889-2393)
- Ákos Végvári (ORCID: https://orcid.org/0000-0002-1287-0906)
- Alexander Espinosa (ORCID: https://orcid.org/0000-0003-1107-776X)
- Lara Mentlein
- Guðný Ella Thorlacius (ORCID: https://orcid.org/0000-0001-8997-4327)
- Marie Wahren‐Herlenius (ORCID: https://orcid.org/0000-0002-0915-7245)
- Elina Richardsdotter Andersson
- Vijole Ottosson
- Vaishnavi Srinivasan Iyer (ORCID: https://orcid.org/0000-0003-1083-8950)
- Tilen Tršelič (ORCID: https://orcid.org/0009-0006-0316-8847)
- Sanjaykumar V. Boddul (ORCID: https://orcid.org/0000-0002-0711-1147)
- Grégoire Martin de Frémont (ORCID: https://orcid.org/0000-0003-3393-3969)
- William A. Nyberg (ORCID: https://orcid.org/0000-0002-9982-1305)
- Maria Sunnerhagen (ORCID: https://orcid.org/0000-0002-0492-5890)
- Diego Velasquez Pulgarin
- Nathalie Pelo
- David Alexander Frei
Institutions
- Linköping University (SE)
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Leibniz Association (DE)
- Integrated Cardio Metabolic Centre (SE)
- University of Bergen (NO)
- University of Regensburg (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1073/pnas.2426917122
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 0.00