Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by impaired T cell effector functions. We have demonstrated impaired protein kinase A-catalyzed protein phosphorylation due to deficient type I protein kinase A (PKA-I) isozyme activity. Deficient isozyme activity predominantly reflects markedly reduced or absent type I regulatory beta subunit protein (RIbeta). This application will investigate the hypothesis that deficient PKA-I isozyme activity is an integral signaling disorder that results in impaired CD4+,CD45RA/RO+- and CD8+,CD45RA/RO+-mediated helper and cytotoxic functions, respectively, which can be partially reconstituted by restoring physiologic PKA-I activity. Our specific aims are: (1) To investigate the role proteolysis/ubiquitination and translational silencing as mechanisms regulating RIbeta protein turnover in T cell lines and normal T cells and to investigate the role of abnormal proteolysis/ubiquitination and/or translational silencing in reduced/absent RIbeta protein expression in SLE T cells. (2) To determine whether deficient PKA-I activity affects all T cells or a specific T cell subset and its relationship to CD59 v expression. (3) To examine the role of the RIbeta2C2 holoenzyme in T cell effector functions in SLE and normal T cells. (4) To perform SLE multiplex family studies to determine (4a) The prevalence of RIbeta protein deficiency. (4a) Whether deficient PKA-I activity due to reduced/absent RIbeta protein is a heritable disorder in families of lupus probands. Thus, the significance of this research is its potential to explain how defective signaling circuitry within the T cell can lead to the aberrant T cell effector functions that result in lupus immunopathogenesis.