miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways.
miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways.
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DOI：
10.1371/journal.pone.0131823
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sommers CL
中科院分区：
文献类型：
--
作者：
Rouquette-Jazdanian AK;Kortum RL;Li W;Merrill RK;Nguyen PH;Samelson LE;Sommers CL
T细胞活化接头（LAT）是T细胞功能所必需的衔接蛋白。具有LAT突变的敲入小鼠损害钙流，发展为致命的CD 4+淋巴组织增生性疾病。miR-155是与包括淋巴瘤和白血病在内的许多癌症中的过度增殖相关的微小RNA，并且在突变LAT T细胞中过表达。为了测试miR-155是否仅仅是T细胞活化的指示，或者它是否有助于突变LAT小鼠中的淋巴组织增生性疾病，我们将LAT突变体和miR-155缺陷小鼠杂交。miR-155缺陷通过刺激BIM依赖性CD 4 + T细胞凋亡显著抑制淋巴增殖性疾病，即使在双突变CD 4 + T细胞中ERK活化和T细胞增殖增加。Bim/Bcl 2l 11表达由叉头转录因子FOXO 3激活。使用miR-155缺陷的LAT突变T细胞作为发现工具，我们发现了两个影响T细胞中FOXO 3核转位和激活的相关途径。一种途径由肌醇磷酸酶SHIP-1和丝氨酸/苏氨酸激酶AKT和PDK 1介导。另一个途径涉及PAK 1和JNK激酶激活。我们通过激酶mTOR定义了两条通路之间的串扰，该激酶稳定PAK 1。这项研究确立了PAK 1在T细胞凋亡中的作用，这与其先前在T细胞增殖中的作用形成对比。此外，miR-155调节T细胞中PAK 1介导的增殖和凋亡之间的微妙平衡，影响淋巴器官的大小和功能。
Linker for Activation of T cells (LAT) is an adapter protein that is essential for T cell function. Knock-in mice with a LAT mutation impairing calcium flux develop a fatal CD4+ lymphoproliferative disease. miR-155 is a microRNA that is correlated with hyperproliferation in a number of cancers including lymphomas and leukemias and is overexpressed in mutant LAT T cells. To test whether miR-155 was merely indicative of T cell activation or whether it contributes to lymphoproliferative disease in mutant LAT mice, we interbred LAT mutant and miR-155-deficient mice. miR-155 deficiency markedly inhibited lymphoproliferative disease by stimulating BIM-dependent CD4+ T cell apoptosis, even though ERK activation and T cell proliferation were increased in double mutant CD4+ T cells. Bim/Bcl2l11 expression is activated by the forkhead transcription factor FOXO3. Using miR-155-deficient, LAT mutant T cells as a discovery tool, we found two connected pathways that impact the nuclear translocation and activation of FOXO3 in T cells. One pathway is mediated by the inositide phosphatase SHIP-1 and the serine/threonine kinases AKT and PDK1. The other pathway involves PAK1 and JNK kinase activation. We define crosstalk between the two pathways via the kinase mTOR, which stabilizes PAK1. This study establishes a role for PAK1 in T cell apoptosis, which contrasts to its previously identified role in T cell proliferation. Furthermore, miR-155 regulates the delicate balance between PAK1-mediated proliferation and apoptosis in T cells impacting lymphoid organ size and function.
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影响因子：
11.2
作者：
Cubillos-Ruiz JR;Baird JR;Tesone AJ;Rutkowski MR;Scarlett UK;Camposeco-Jacobs AL;Anadon-Arnillas J;Harwood NM;Korc M;Fiering SN;Sempere LF;Conejo-Garcia JR
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Conejo-Garcia JR
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影响因子：
7.8
作者：
Gilley, Jonathan;Coffer, Paul J;Ham, Jonathan
通讯作者：
Ham, Jonathan
影响因子：
7.2
作者：
Balagopalan, Lakshmi;Coussens, Nathan P.;Sommers, Connie L.
通讯作者：
Sommers, Connie L.
影响因子：
7.7
作者：
Herold, Marco J.;Rohrbeck, Leona;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.