Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 30, Pages 12443-12448Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103915108
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Funding
- National Institutes of Health [R01 A1068787]
- Arthritis Foundation
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The activity and substrate specificity of the ubiquitously expressed phosphatase PP2A is determined by the type of regulatory (B) subunit that couples to the catalytic/scaffold core of the enzyme. We determined that the B beta subunit (PPP2R2B) is expressed in resting T cells, its transcription is down-regulated during T-cell activation, and up-regulated in conditions of low IL-2. Specifically, high levels of PP2A B beta were produced during IL-2 deprivation-induced apoptosis, whereas Fas ligation had no effect. Forced expression of the B beta subunit in primary human T cells was sufficient to induce apoptosis, whereas silencing using siRNA protected activated T cells from IL-2 withdrawal-induced cell death. Because T-cell apoptosis is known to be altered in T cells from patients with systemic lupus erythematosus, we analyzed the regulation of PP2A B beta in this autoimmune disease. We found that levels of PP2A B beta did not increase upon IL-2 deprivation in 50% of the patients. Remarkably, this defect was accompanied by resistance to apoptosis. Importantly, kinetics of cell death were normal in cells of patients that up-regulated PP2A B beta in a normal manner. We have identified a unique role for the phosphatase PP2A, particularly the holoenzyme formed by PP2A B beta. B beta appears to trigger apoptosis of T cells in the absence of IL-2 and probably contributes to the termination of a no-longer-needed immune response. We propose that defective production of PP2A B beta upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients.
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