Centro Nacional de Enfermedades Reumáticas, Division of Rheumatology, Hospital Universitario de Caracas, Universidad Central de Venezuela, Ciudad Universitaria, Caracas, Venezuela.
Clin Immunol. 2012 Mar;142(3):243-51. doi: 10.1016/j.clim.2011.12.010. Epub 2011 Dec 30.
Systemic lupus erythematosus (SLE) is characterized by abnormal signal transduction mechanisms in T lymphocytes. Linker for activation of T cells (LAT) couples TCR/CD3 activation with downstream signaling pathways. We reported diminished ERK 1/2 kinase activity in TCR/CD3 stimulated lupus T cells. In this study we evaluated the expression, phosphorylation, lipid raft and immunological synapse (IS) localization and colocalization of LAT with key signalosome molecules. We observed a diminished expression and an abnormal localization of LAT in lipid rafts and at the IS in activated lupus T cells. LAT phosphorylation, capture by GST-Grb2 fusion protein, and coupling to Grb2 and PLCγ1, was similar in healthy control and lupus T cells. Our results suggest that an abnormal localization of LAT within lipid rafts and its accelerated degradation after TCR/CD3 activation may compromise the assembly of the LAT signalosome and downstream signaling pathways required for full MAPK activation in lupus T cells.
系统性红斑狼疮（SLE）的特征是 T 淋巴细胞中异常的信号转导机制。T 细胞激活衔接蛋白（LAT）将 TCR/CD3 激活与下游信号通路偶联。我们报道了在 TCR/CD3 刺激的狼疮 T 细胞中 ERK1/2 激酶活性降低。在这项研究中，我们评估了 LAT 与关键信号体分子的表达、磷酸化、脂筏和免疫突触（IS）定位和共定位。我们观察到在激活的狼疮 T 细胞中，LAT 在脂筏和 IS 中的表达和异常定位减少。LAT 的磷酸化、与 GST-Grb2 融合蛋白的结合以及与 Grb2 和 PLCγ1 的偶联在健康对照组和狼疮 T 细胞中相似。我们的结果表明，LAT 在脂筏内的异常定位及其在 TCR/CD3 激活后加速降解可能会破坏 LAT 信号体的组装以及下游信号通路，从而影响狼疮 T 细胞中 MAPK 的完全激活。
