Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Tilen Tršelič
Nathalie Pelo
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Gregoire Martin de Fremont
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Vaishnavi S. Iyer
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Elina Richardsdotter Andersson
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Vijole Ottosson
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
David Alexander Frei
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Elisa Baas
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
William A. Nyberg
Guðný Ella Thorlacius
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Lara Mentlein
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Sanjaykumar V. Boddul
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Ioana Sandu
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Diego Velasquez Pulgarin
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Ákos Végvári
Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
Carmen Gerlach
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Fredrik Wermeling
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital
Maria Sunnerhagen
Department of Physics, Chemistry and Biology, Linköping University
Björn Wallner
Department of Physics, Chemistry and Biology, Linköping University
Alexander Espinosa
Marie Wahren-Herlenius
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital