Protein kinase A RI beta subunit deficiency in lupus T lymphocytes: bypassing a block in RI beta translation reconstitutes protein kinase A activity and augments IL-2 production.
A profound deficiency of type I protein kinase A (PKA-I or RIalpha/beta2C2) phosphotransferase activity occurs in the T lymphocytes of 80% of subjects with systemic lupus erythematosus (SLE), an autoimmune disorder of unknown etiology. This isozyme deficiency is predominantly the product of reduced or absent beta isoform of the type I regulatory subunit (RIbeta). Transient transfection of RIbeta cDNAs from SLE subjects into autologous T cells that do not synthesize the RIbeta subunit bypassed the block, resulting in RIbeta subunit synthesis and restoration of the PKA-Ibeta (RIbeta2C2) holoenzyme. Transfected T cells activated via the T cell surface receptor complex revealed a significant increase of cAMP-activatable PKA activity that was associated with a significant increase in IL-2 production. These data demonstrate that a disorder of RIbeta translation exists, and that correction of the PKA-I deficiency may enhance T lymphocyte effector functions in SLE.
Khan
I U
IU
Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Laxminarayana
D
D
Kammer
G M
GM
D002460:Cell Line; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D018076:DNA, Complementary / Q000096:biosynthesis; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007376:Interleukin-2 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification; D011401:Promoter Regions, Genetic / Q000276:immunology; D014176:Protein Biosynthesis / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D014162:Transfection
D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D018076:DNA, Complementary; D007376:Interleukin-2; D007527:Isoenzymes; C517766:PRKAR1B protein, human; D010446:Peptide Fragments; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases