The DEK Nuclear Autoantigen Is a Secreted Chemotactic Factor

Abstract

The nuclear DNA-binding protein DEK is an autoantigen that has been implicated in the regulation of transcription, chromatin architecture, and mRNA processing. We demonstrate here that DEK is actively secreted by macrophages and is also found in synovial fluid samples from patients with juvenile arthritis. Secretion of DEK is modulated by casein kinase 2, stimulated by interleukin-8, and inhibited by dexamethasone and cyclosporine A, consistent with a role as a proinflammatory molecule. DEK is secreted in both a free form and in exosomes, vesicular structures in which transcription-modulating factors such as DEK have not previously been found. Furthermore, DEK functions as a chemotactic factor, attracting neutrophils, CD8⁺ T lymphocytes, and natural killer cells. Therefore, the DEK autoantigen, previously described as a strictly nuclear protein, is secreted and can act as an extracellular chemoattractant, suggesting a direct role for DEK in inflammation.

We thank Gilbert Vaknin, Steve Weiss, Joanne Cleary, and Brian Lane for technical advice and intellectual support, Tom Glaser for the pGNVL3 plasmid, and Donna Gschwend for manuscript preparation. We also thank Gerard Grosveld of St. Jude Children's Research Hospital in Memphis, TN, for rabbit polyclonal anti-DEK antibody, and Lorenzo Pinna of the Universita di Padua, Padua, Italy, for the CK2 blocker TBB.

This work was supported by grants to D.M.M. from the American Cancer Society, the Arthritis Foundation, the Rheumatic Disease Core Center of the University of Michigan (5 P30 AR48310-02), and the General Clinical Research Center at the University of Michigan (M01-RR00042). N.M.-V. was supported by a grant from the Arthritis Foundation and by NIH grant T32CA88784-03 through the University of Michigan Tumor Immunology Training Program. A.P. was supported by Merit Review funding and a Research Enhancement Award Program (REAP) grant from the Department of Veterans Affairs. D.G. was supported by the Cincinnati Children's Hospital Medical Center Research Foundation (Pediatric Rheumatology Tissue Repository, Susan D. Thompson, principal investigator). N.F., M.S.K., and K.S. were supported in part by NIH Training Grant T32 GM07863 through the University of Michigan Medical Scientist Training Program. N.F. was also supported by a Rackham Merit fellowship from the University of Michigan. M.S.K. was additionally supported by a Graduate Research Fellowship from the National Science Foundation. L.P. was supported by Merit Review funding from the Department of Veterans Affairs. J.H.R. was supported by grant AR49907 from the NIH and by funds from the Arthritis Foundation. A.K. was supported by grants AI40987, HL58694, and AR48267 from the NIH and funds from the Arthritis Foundation and the Frederick G. L. Heutwell and William D. Robinson, M.D. Professorship. D.M.M. is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.