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,
*
Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; and
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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-II 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
RIIß2C2 holoenzyme and translocation of the
regulatory (RIIß) subunit from the cytosol to the nucleus. Confocal
immunofluorescence microscopy revealed that the RIIß subunit was
present in 
60% of SLE T cell nuclei compared with only 2–3% of
normal and disease controls. Quantification of nuclear RIIß subunit
protein content by immunoprecipitation and immunoblotting demonstrated
a 54% increase over normal T cell nuclei. Moreover, the RIIß 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 RIIß subunit
and its retention in the nucleus in SLE T cells. Deficient PKA-II
activity may contribute to impaired signaling in SLE T
cells.
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