Association of deficient Type II Protein Kinase A activity with aberrant nuclear translocation of the RIIβ subunit in systemic lupus erythematosus T lymphocytes

N Mishra, IU Khan, GC Tsokos… - The Journal of …, 2000 - journals.aai.org
N Mishra, IU Khan, GC Tsokos, GM Kammer
The Journal of Immunology, 2000journals.aai.org
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 …
Abstract
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 RIIβ 2 C 2 holoenzyme and translocation of the regulatory (RIIβ) subunit from the cytosol to the nucleus. Confocal immunofluorescence microscopy revealed that the RIIβ subunit was present in∼ 60% of SLE T cell nuclei compared with only 2–3% of normal and disease controls. Quantification of nuclear RIIβ subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei. Moreover, the RIIβ 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 RIIβ 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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