2. Academic Validation
  3. Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility

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

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.

Figures
Products