ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells

Abstract 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...

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Autores principales:	Wei Chen, Melanie S. Nyuydzefe, Jonathan M. Weiss, Jingya Zhang, Samuel D. Waksal, Alexandra Zanin-Zhorov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Rho-associated Coiled-coil Kinase (ROCK) Bcl-2 Promoter Selective ROCK Inhibitor Myosin Phosphatase (MYPT) Th2 Skewing Conditions Medicine R Science Q
Acceso en línea:	https://doaj.org/article/161f3b2af832421d851906abac38085c
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spelling	oai:doaj.org-article:161f3b2af832421d851906abac38085c2021-12-02T15:08:13ZROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells10.1038/s41598-018-35109-92045-2322https://doaj.org/article/161f3b2af832421d851906abac38085c2018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-35109-9https://doaj.org/toc/2045-2322Abstract 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.Wei ChenMelanie S. NyuydzefeJonathan M. WeissJingya ZhangSamuel D. WaksalAlexandra Zanin-ZhorovNature PortfolioarticleRho-associated Coiled-coil Kinase (ROCK)Bcl-2 PromoterSelective ROCK InhibitorMyosin Phosphatase (MYPT)Th2 Skewing ConditionsMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Rho-associated Coiled-coil Kinase (ROCK) Bcl-2 Promoter Selective ROCK Inhibitor Myosin Phosphatase (MYPT) Th2 Skewing Conditions Medicine R Science Q
spellingShingle	Rho-associated Coiled-coil Kinase (ROCK) Bcl-2 Promoter Selective ROCK Inhibitor Myosin Phosphatase (MYPT) Th2 Skewing Conditions Medicine R Science Q Wei Chen Melanie S. Nyuydzefe Jonathan M. Weiss Jingya Zhang Samuel D. Waksal Alexandra Zanin-Zhorov ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
description	Abstract 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.
format	article
author	Wei Chen Melanie S. Nyuydzefe Jonathan M. Weiss Jingya Zhang Samuel D. Waksal Alexandra Zanin-Zhorov
author_facet	Wei Chen Melanie S. Nyuydzefe Jonathan M. Weiss Jingya Zhang Samuel D. Waksal Alexandra Zanin-Zhorov
author_sort	Wei Chen
title	ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
title_short	ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
title_full	ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
title_fullStr	ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
title_full_unstemmed	ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
title_sort	rock2, but not rock1 interacts with phosphorylated stat3 and co-occupies th17/tfh gene promoters in th17-activated human t cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/161f3b2af832421d851906abac38085c
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ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells

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