Deficient protein kinase a in systemic lupus erythematosus: a disorder of T lymphocyte signal transduction.
Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disease characterized by impaired T lymphocyte immune effector functions. We have identified a disorder of signal transduction in SLE T cells involving the cyclic AMP/protein kinase A (cAMP/PKA) pathway. Cyclic AMP-stimulated PKA-catalyzed protein phosphorylation is markedly diminished owing to profound deficiencies of both type I (PKA-I) and type II (PKA-II) isozyme activities. Deficient PKA-I isozyme is characterized by a significant reduction in the amount of type I regulatory beta subunit (RI beta) steady state mRNA by competitive polymerase chain reaction. This is associated with a 30% decrease in RI alpha protein and a 65% reduction in RI beta protein. Indeed, T cells from approximately 25% of SLE subjects have no detectable RI beta protein. Transient transfection of T cells not expressing RI beta protein with autologous SLE RI beta cDNA bypassed the block in translation, reconstituting PKA activity and augmenting IL-2 production. Of importance was the initial identification of novel RI alpha mRNA mutations characterized by heterogeneous transcript mutations, including deletions, transitions, and transversions. Most mutations are clustered adjacent to GAGAG motifs and CT repeats. By contrast, deficient PKA-II activity is the result of spontaneous dissociation of the cytosolic RII beta(2)C(2) holoenzyme, aberrant RII beta translocation to the nucleus from the cytosol, and retention of RII beta in the nucleus. In conclusion, distinct mechanisms account for deficient PKA-I and PKA-II isozyme activities in SLE T cells.
Kammer
Gary M
GM
Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. gmkammer@wfubmc.edu
D000242:Cyclic AMP / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000276:immunology; D015290:Second Messenger Systems / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology*
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D007376:Interleukin-2; D007527:Isoenzymes; C517834:PRKAR1A protein, human; C517766:PRKAR1B protein, human; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases