Human T-lymphotropic virus type 1 p30 interacts with REGgamma and modulates ATM (ataxia telangiectasia mutated) to promote cell survival.
ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is a causative agent of adult T cell leukemia/lymphoma and a variety of inflammatory disorders. HTLV-1 encodes a nuclear localizing protein, p30, that selectively alters viral and cellular gene expression, activates G(2)-M cell cycle checkpoints, and is essential for viral spread. Here, we used immunoprecipitation and affinity pulldown of ectopically expressed p30 coupled with mass spectrometry to identify cellular binding partners of p30. Our data indicate that p30 specifically binds to cellular ATM (ataxia telangiectasia mutated) and REGγ (a nuclear 20 S proteasome activator). Under conditions of genotoxic stress, p30 expression was associated with reduced levels of ATM and increased cell survival. Knockdown or overexpression of REGγ paralleled p30 expression, suggesting an unexpected enhancement of p30 expression in the presence of REGγ. Finally, size exclusion chromatography revealed the presence of p30 in a high molecular mass complex along with ATM and REGγ. On the basis of our findings, we propose that HTLV-1 p30 interacts with ATM and REGγ to increase viral spread by facilitating cell survival.
SourceAvailable from: Stefan Rödiger[Show abstract] [Hide abstract]
ABSTRACT: PA28gamma (also known as Ki, REG gamma, PMSE3), a member of the ubiquitin-and ATP-independent proteasome activator family 11S, has been proved to show proteasome-dependent and -independent effects on several proteins including tumor suppressor p53, cyclin-dependent kinase inhibitor p21 and steroid receptor co-activator 3 (SCR-3). Interestingly, PA28gamma is overexpressed in pathological tissue of various cancers affecting e. g. breast, bowl and thyroids. Furthermore, anti-PA28gamma autoantibodies have been linked to several autoimmune disorders. The aim of this study was to develop and evaluate a novel and sensitive PA28gamma sandwich ELISA for the quantification of PA28gamma serum levels in patients with cancer and autoimmune diseases for diagnostic and prognostic purposes. PA28gamma-specific polyclonal antibodies and recombinant His-tagged PA28gamma were purified and used to develop a sandwich ELISA for the detection of circulating PA28gamma. With this new assay, PA28gamma serum levels of patients with various cancers, rheumatoid arthritis (RA), Sjogren's syndrome (SS), adult-onset Still's disease (AOSD) and different connective-tissue diseases (CTD) were compared with healthy control subjects. Anti-PA28gamma autoantibodies were additionally confirmed using a newly developed microbead assay. The developed PA28gamma sandwich ELISA showed a high specificity with a detection limit of 3 ng/ml. A significant up-regulation of circulating PA28gamma was detected in the sera of patients with cancer, RA, SS and CTD. A significant correlation was observed dependent on age as well as anti-PA28gamma autoantibody levels with circulating PA28gamma protein levels. Furthermore, PA28gamma serum levels showed a correlation with disease activity in patients with RA under treatment with the T-cell directed biological compound abatacept according to disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR). The application of PA28gamma as a novel biomarker for diagnostic purposes of a specific disease is limited, since elevated levels were observed in different disorders. However, the correlation with disease activity in patients with RA suggests a prognostic value, which needs to be addressed by further studies. Therefore our results show that PA28gamma is a useful marker which should be included in studies related to novel treatments, e.g. abatacept.BMC Musculoskeletal Disorders 12/2014; 15(1):414. DOI:10.1186/1471-2474-15-414 · 1.90 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Bovine leukemia virus (BLV) and human T-lymphotrophic virus type-1 (HTLV-1) are related retroviruses associated with persistent and lifelong infections and a low incidence of lymphomas within their hosts. Both viruses can be spread through contact with bodily fluids containing infected cells, most often from mother to offspring through breast milk. Each of these complex retroviruses contains typical gag, pol, and env genes but also unique, nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the pathogenesis of each virus. Comparisons of BLV and HTLV-1 provide insights into mechanisms of spread and tumor formation, as well as potential approaches to therapeutic intervention against the infections.02/2014; 2:189-208. DOI:10.1146/annurev-animal-022513-114117