The Regulatory Subunit PPP2R2A of PP2A Enhances Th1 and Th17 Differentiation through Activation of the GEF-H1/RhoA/ROCK Signaling Pathway.
The Regulatory Subunit PPP2R2A of PP2A Enhances Th1 and Th17 Differentiation through Activation of the GEF-H1/RhoA/ROCK Signaling Pathway.
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PP 2A的调节亚基PPP 2 R2 A通过激活GEF-H1/RhoA/ROCK信号通路增强Th 1和Th 17分化。
DOI：
10.4049/jimmunol.2001266
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发表时间：
2021-04-15
期刊：
影响因子：
--
通讯作者：
Tsokos GC
中科院分区：
文献类型：
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作者：
Pan W;Nagpal K;Suárez-Fueyo A;Ferretti A;Yoshida N;Tsokos MG;Tsokos GC
蛋白磷酸酶2A（PP 2A）是一种广泛表达的丝氨酸/苏氨酸磷酸酶，由骨架、催化和多个调节亚基组成。我们先前已经表明，PP 2A催化亚基在系统性红斑狼疮（SLE）患者的T细胞中增加，并通过增强T细胞中Rho相关激酶（ROCK）的活性来促进IL-17的产生。然而，PP 2A调节ROCK活性的分子机制尚不清楚。在这里，我们表明PP 2A调节亚基PPP 2 R2 A在SLE患者的T细胞中增加，并在Ser 885处结合，去磷酸化和激活鸟嘌呤核苷酸交换因子GEF-H1，这反过来又增加了T细胞中RhoA-GTP的水平和ROCK的活性。小鼠T细胞中的遗传PPP 2 R2 A缺陷减少了Th 1和Th 17，但不减少调节性T细胞分化，并且当用髓鞘少突胶质细胞糖蛋白肽免疫时，具有T细胞特异性PPP 2 R2 A缺陷的小鼠显示较少的自身免疫。我们的研究表明，PPP 2 R2 A是规定PP 2A导向的增强的Th 1和Th 17分化的调节亚基，因此它代表了与Th 1和Th 17细胞扩增相关的病理学的治疗靶点。
Protein phosphatase 2A (PP2A) composed of a scaffold, a catalytic and multiple regulatory subunits is a ubiquitously expressed serine/threonine phosphatase. We have previously shown that the PP2A catalytic subunit is increased in T cells from patients with systemic lupus erythematosus (SLE) and promotes IL-17 production by enhancing the activity of Rho-associated kinase (ROCK) in T cells. However, the molecular mechanism whereby PP2A regulates ROCK activity is unknown. Here we show that the PP2A regulatory subunit PPP2R2A is increased in T cells from people with SLE and binds to, dephosphorylates and activates the guanine nucleotide exchange factor GEF-H1 at Ser885 which in turn increases the levels of RhoA-GTP and the activity of ROCK in T cells. Genetic PPP2R2A deficiency in murine T cells reduced Th1 and Th17 but not regulatory T cell differentiation and mice with T cell-specific PPP2R2A deficiency displayed less autoimmunity when immunized with myelin oligodendrocyte glycoprotein peptide. Our studies indicate that PPP2R2A is the regulatory subunit that dictates the PP2A-directed enhanced Th1 and Th17 differentiation and therefore it represents a therapeutic target for pathologies linked to Th1 and Th17 cell expansion.
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DOI：
10.4049/jimmunol.1200143
发表时间：
2012-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Crispín JC;Apostolidis SA;Rosetti F;Keszei M;Wang N;Terhorst C;Mayadas TN;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
2.9
作者：
Amano, Mutsuki;Nakayama, Masanori;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
DOI：
10.1083/jcb.201603109
发表时间：
2016-10-10
期刊：
The Journal of cell biology
影响因子：
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作者：
Fine N;Dimitriou ID;Rullo J;Sandí MJ;Petri B;Haitsma J;Ibrahim H;La Rose J;Glogauer M;Kubes P;Cybulsky M;Rottapel R
通讯作者：
Rottapel R
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
82.9
作者：
通讯作者：
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