Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit.
DNA-dependent protein kinase (DNA-PK) consists of a DNA binding subunit (Ku autoantigen), and a catalytic subunit (DNA-PKcs). In the present study, human autoantibodies that recognize novel antigenic determinants of DNA-PK were identified. One type of autoantibody stabilized the interaction of DNA-PKcs with Ku and recognized the DNA-PKcs -Ku complex, but not bio-chemically purified DNA-PKcs. Another type recognized purified DNA-PKcs. Autoantibodies to Ku (p70/p80 heterodimer), 'stabilizing' antibodies, and antibodies to DNA-PKcs comprise a linked autoantibody set, since antibodies recognizing purified DNA-PKcs were strongly associated with stabilizing antibodies, whereas stabilizing antibodies were strongly associated with anti-Ku. This hierarchical pattern of autoantibodies specific for components of DNA-PK (anti-Ku > stabilizing antibodies > anti-DNA-PKcs) may have implications for the pathogenesis of autoimmunity to DNA-PK and other chromatin particles. The data raise the possibility that altered antigen processing and/or stabilization of the DNA-PKcs-Ku complex due to autoantibody binding could play a role in spreading autoimmunity from Ku to the weakly associated antigen DNA-PKcs.
Satoh
M
M
Department of Medicine, University of North Carolina, Chapel Hill 27599-7280, USA.
Ajmani
A K
AK
Stojanov
L
L
Langdon
J J
JJ
Ogasawara
T
T
Wang
J
J
Dooley
M A
MA
Richards
H B
HB
Winfield
J B
JB
Carter
T H
TH
Reeves
W H
WH
D000937:Antigen-Antibody Reactions; D034961:Antigens, Nuclear; D001323:Autoantibodies / Q000097:blood / Q000737:chemistry / Q000502:physiology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000276:immunology; D004265:DNA Helicases; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006657:Histones / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry; D015151:Immunoblotting; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000276:immunology* / Q000502:physiology*
D034961:Antigens, Nuclear; D001323:Autoantibodies; D001324:Autoantigens; D004268:DNA-Binding Proteins; D006657:Histones; D007106:Immune Sera; D009687:Nuclear Proteins; D004247:DNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen