Association of deficient type II protein kinase a activity with aberrant nuclear translocation of the RIIβ subunit in systemic lupus erythematosus T lymphocytes

Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by abnormal T cell signal transduction and altered T cell effector functions, We have previously observed a profound deficiency of total protein kinase A (PKA) phosphotransferase activity in SLE T cells. Here we examined whether reduced total PKA activity In SLE T cells is in part the result of deficient type II PKA (PKA-II) isozyme activity. The mean PKA-II activity in SLE T cells was 61% of normal control T cells. The prevalence of deficient PKA-IZ activity in 35 SLE subjects was 37%, Deficient Isozyme activity was persistent over time and was unrelated to SLE disease activity. Reduced PKA-II activity was associated with spontaneous dissociation of the cytosolic RII beta C-2(2) holoenzyme and translocation of the regulatory (RII beta) subunit from the cytosol to the nucleus, Confocal immunofluorescence microscopy revealed that the RII beta subunit was present in similar to 60% of SLE T cell nuclei compared with only 2-3% of normal and disease controls, Quantification of nuclear RII beta subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei, Moreover, the RII beta subunit was retained in SLE T cell nuclei, failed to relocate to the cytosol, and was associated with a persistent deficiency of PKA-II activity, In conclusion, we describe a novel mechanism of deficient PKA-II isozyme activity due to aberrant nuclear translocation of the RII beta subunit and its retention in the nucleus in SLE T cells. Deficient PKA-II activity may contribute to impaired signaling in SLE T cells.