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

Systemic lupus erythematosus (SLE) is an autoimmune disorder of indetermina te etiology characterized by abnormal T cell signal transduction and altere d T cell effector functions, We have previously observed a profound deficie ncy of total protein kinase A (PKA) phosphotransferase activity in SLE T ce lls. 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%, Deficie nt Isozyme activity was persistent over time and was unrelated to SLE disea se activity. Reduced PKA-II activity was associated with spontaneous dissoc iation of the cytosolic RII beta C-2(2) holoenzyme and translocation of the regulatory (RII beta) subunit from the cytosol to the nucleus, Confocal im munofluorescence 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 an d disease controls, Quantification of nuclear RII beta subunit protein cont ent by immunoprecipitation and immunoblotting demonstrated a 54% increase o ver normal T cell nuclei, Moreover, the RII beta subunit was retained in SL E 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 n ovel 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.