Mechanisms of deficient type I protein kinase A activity in lupus T lymphocytes.
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune response to antigen results in exaggerated CD4(+) T helper and diminished CD8(+) T cytotoxic responses. To determine the mechanisms underlying impaired T cell effector functions, we have investigated the cAMP/protein kinase A (cAMP/PKA) signaling pathway. The results demonstrate that diminished PKA-catalyzed protein phosphorylation is the result of deficient type I (PKA-I) and type II (PKA-II) isozyme-specific activities. The prevalence of deficient PKA-I and PKA-II activities in SLE T cells is approximately 80% and 40%, respectively. Diminished PKA-I activities are not associated with disease activity and appear to be stable over time. Two disparate mechanisms account for these low PKA-I and PKA-II isozyme activities. Moreover, novel transcript mutations of the RI alpha gene have been identified that are characterized by deletions, transitions, and transversions. Most mutations are clustered adjacent to GAGAG motifs and CT repeats. In conclusion, aberrant signaling via the cAMP/PKA pathway occurs in SLE T cells, and this is proposed to contribute to abnormal T cell effector functions.
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@hotmail.com
Laxminarayana
Dama
D
Khan
Islam U
IU
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology*; D010766:Phosphorylation; D017354:Point Mutation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D015854:Up-Regulation
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases