ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells.
ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells.
复制标题
DOI：
10.1038/s41598-018-35109-9
复制
发表时间：
2018-11-09
影响因子：
4.6
通讯作者：
Zanin-Zhorov A
中科院分区：
文献类型：
--
作者：
Chen W;Nyuydzefe MS;Weiss JM;Zhang J;Waksal SD;Zanin-Zhorov A
Rho相关卷曲螺旋激酶（ROCK）2靶向下调动物模型和患者的自身免疫反应，但潜在的分子机制仍然是一个谜。我们报道了ROCK 2结合磷酸化的STAT 3，其激酶活性控制了在T辅助细胞17（TH 17）-偏斜过程中人CD 4 + T细胞中ROCK 2/STAT 3/JAK 2复合物的形成和最佳STAT 3磷酸化。此外，染色质免疫沉淀测序（ChIP-seq）分析显示，在全基因组范围内，约70%的ROCK 2和STAT 3峰重叠并共定位于控制TH 17和T滤泡辅助细胞（TFH）功能的几个关键基因。具体地，通过ChIP-qPCR分析验证了R 0 CK 2和STAT 3在Irf 4和Bcl 6基因上的共占据。此外，通过STAT 3沉默以及通过选择性ROCK 2抑制剂减弱ROCK 2与Irf 4和Bcl 6启动子两者的结合。因此，本研究证明了先前未鉴定的证据，即ROCK 2介导的细胞质中的信号传导为核ROCK 2提供了正前馈信号，以通过STAT 3募集到染色质，并可能调节TH 17/TFH基因转录。
Rho-associated coiled-coil kinase (ROCK)2 targeting down-regulates autoimmune responses in animal models and patients, however the underlying molecular mechanism is still an enigma. We report that ROCK2 binds phosphorylated-STAT3 and its kinase activity controls the formation of ROCK2/STAT3/JAK2 complex and optimal STAT3 phosphorylation in human CD4+ T cells during T helper 17 (TH17)-skewing. Moreover, chromatin-immunoprecipitation sequencing (ChIP-seq) analysis revealed that, genome-wide, about 70% of ROCK2 and STAT3 peaks overlapped and co-localized to several key genes controlling TH17 and T follicular helper (TFH) cell functions. Specifically, the co-occupancy of ROCK2 and STAT3 on the Irf4 and Bcl6 genes was validated by ChIP-qPCR analysis. Furthermore, the binding of ROCK2 to both the Irf4 and Bcl6 promoters was attenuated by STAT3 silencing as well as by selective ROCK2 inhibitor. Thus, the present study demonstrated previously unidentified evidence that ROCK2-mediated signaling in the cytosol provides a positive feed-forward signal for nuclear ROCK2 to be recruited to the chromatin by STAT3 and potentially regulates TH17/TFH gene transcription.
登录
查看更多内容
DOI：
10.4049/jimmunol.0903006
发表时间：
2010-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Radojcic V;Pletneva MA;Yen HR;Ivcevic S;Panoskaltsis-Mortari A;Gilliam AC;Drake CG;Blazar BR;Luznik L
通讯作者：
Luznik L
影响因子：
4.8
作者：
Kureishi, Y;Kobayashi, S;Ito, M
通讯作者：
Ito, M
DOI：
10.1126/science.1176676
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nurieva RI;Chung Y;Martinez GJ;Yang XO;Tanaka S;Matskevitch TD;Wang YH;Dong C
通讯作者：
Dong C
DOI：
10.1084/jem.20141380
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hatzi K;Nance JP;Kroenke MA;Bothwell M;Haddad EK;Melnick A;Crotty S
通讯作者：
Crotty S
影响因子：
4.8
作者：
Debidda, M;Wang, L;Zheng, Y
通讯作者：
Zheng, Y