Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A
Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A
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DOI：
10.4049/jimmunol.168.10.5070
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Kuchroo, VK
中科院分区：
文献类型：
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作者：
Baroja, ML;Vijayakrishnan, L;Kuchroo, VK
丝氨酸/苏氨酸磷酸酶2A（MA）的催化亚基可以与CTLA-4的胞质尾区相互作用。然而，这种相互作用的分子基础和生物学意义尚不清楚。在这项研究中，我们报告，PP 2A（PP 2AA）的调节亚基也与CTLA-4的胞质尾相互作用。有趣的是，TCR连接诱导PP 2AA的酪氨酸磷酸化及其在共连接时从CTLA-4解离。PP 2AA和CTLA-4之间的关联涉及CTLA-4的胞质尾区的质膜部分中的保守的三赖氨酸基序。这些赖氨酸残基的突变阻止了PP 2AA的结合，并增强了CTLA-4对IL-2基因转录的抑制，表明PP 2A抑制CTLA-4功能。我们的数据表明，在CTLA-4中的赖氨酸丰富的基序可用于识别小分子，阻止其结合PP 2A和作为CTLA-4功能的激动剂。
The catalytic subunit of the serine/threonine phosphatase 2A (MA) can interact with the cytoplasmic tail of CTLA-4. However, the molecular basis and the biological significance of this interaction are unknown. In this study, we report that the regulatory subunit of PP2A (PP2AA) also interacts with the cytoplasmic tail of CTLA-4. Interestingly, TCR ligation induces tyrosine phosphorylation of PP2AA and its dissociation from CTLA-4 when coligated. The association between PP2AA and CTLA-4 involves a conserved three-lysine motif in the juxtamembrane portion of the cytoplasmic tail of CTLA-4. Mutations of these lysine residues prevent the binding of PP2AA and enhance the inhibition of IL-2 gene transcription by CTLA-4, indicating that PP2A represses CTLA-4 function. Our data imply that the lysine-rich motif in CTLA-4 may be used to identify small molecules that block its binding to PP2A and act as agonists for CTLA-4 function.