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

  • Proc Natl Acad Sci U S A. 2025 Oct 7;122(40):e2426917122. doi: 10.1073/pnas.2426917122.
Tilen Tršelič  1 ,  Nathalie Pelo  1 ,  Gregoire Martin de Fremont  1 ,  Vaishnavi S Iyer  1 ,  Elina Richardsdotter Andersson  1 ,  Vijole Ottosson  1 ,  David Alexander Frei  1 ,  Elisa Baas  1 ,  William A Nyberg  1  2 ,  Guðný Ella Thorlacius  1 ,  Lara Mentlein  1 ,  Sanjaykumar V Boddul  1 ,  Ioana Sandu  1 ,  Diego Velasquez Pulgarin  1 ,  Ákos Végvári  3 ,  Carmen Gerlach  1  4  5 ,  Fredrik Wermeling  1 ,  Maria Sunnerhagen  6 ,  Björn Wallner  6 ,  Alexander Espinosa  1 ,  Marie Wahren-Herlenius  1  7
Affiliations
  • 1. Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 77, Sweden.
  • 2. Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge 141 52, Sweden.
  • 3. Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77, Sweden.
  • 4. Division of Tailored T-cell diversity, Leibniz Institute for Immunotherapy (LIT), Regensburg 93053, Germany.
  • 5. Department of Immune Medicine, Faculty of Medicine, University of Regensburg, Regensburg 93053, Germany.
  • 6. Department of Physics, Chemistry and Biology, Linköping University, Linköping 581 83, Sweden.
  • 7. Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
PMID: 41042840 DOI: 10.1073/pnas.2426917122
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.

Keywords
DIORA1; FAM167A; MRCK kinases; autoimmunity; cell motility.
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