Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization.
Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization.
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DOI：
10.4049/jimmunol.1302923
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发表时间：
2014-07-01
期刊：
影响因子：
--
通讯作者：
Vyas YM
中科院分区：
文献类型：
--
作者：
Sadhukhan S;Sarkar K;Taylor M;Candotti F;Vyas YM
威斯科特-奥尔德里奇综合征蛋白 (WASp) 的缺陷是 WAS 发展的基础，WAS 是一种 X 连锁免疫缺陷和儿童自身免疫性疾病。 WASp 家族的成核促进因子 (NPF) 通过 VCA 结构域在胞质溶胶中生成 F-肌动蛋白，并支持细胞核中 RNA 聚合酶 II 依赖性转录。然而，核-WASp 是否需要整合其 ARP2/3 依赖性细胞质功能来重新编程基因转录，仍然悬而未决。利用人类T辅助（TH）细胞分化模型，我们发现WASp具有功能性核定位（NLS）和核退出（NES）序列，因此其对转录的影响主要在其通过核孔进入和退出核的水平上进行控制。人 WASp 不利用其 VCA 依赖性、ARP2/3 驱动的细胞质效应机制来支持 TH1 倾斜细胞核中的组蛋白 H3K4 甲基转移酶活性。因此，核-WASp的孤立缺陷足以损害TH1偏向细胞中TBX21和IFNG启动子的转录重编程，而胞质-WASp的孤立缺陷不会损害该过程。相比之下，TH2 倾斜细胞中 WASp 的核存在量很小，其丢失不会损害 GATA3 和 IL4 启动子的转录重编程。我们的研究揭示了核 WASp 在 TH1 基因激活中的独立于 ARP2/3:VCA 的功能，该功能与其在肌动蛋白聚合中的细胞质作用无关。
Defects in Wiskott-Aldrich Syndrome protein (WASp) underlie development of WAS, an X-linked immunodeficiency and autoimmunity disorder of childhood. Nucleation-promoting factors (NPFs) of the WASp-family generate F-actin in the cytosol via the VCA-domain and support RNA polymerase II-dependent transcription in the nucleus. Whether nuclear-WASp requires the integration of its ARP2/3-dependent cytoplasmic function to reprogram gene transcription, however, remains unresolved. Using the model of human T helper (TH) cell differentiation, we find that WASp has a functional nuclear localizing (NLS) and nuclear exit (NES) sequences and accordingly its effects on transcription are controlled mainly at the level of its nuclear entry and exit via the nuclear pore. Human WASp does not utilize its VCA-dependent, ARP2/3-driven, cytoplasmic effector mechanisms to support histone H3K4 methyltransferase activity in the nucleus of TH1-skewed cells. Accordingly, an isolated deficiency of nuclear-WASp is sufficient to impair the transcriptional reprogramming of TBX21 and IFNG promoters in TH1-skewed cells, whereas, an isolated deficiency of cytosolic-WASp does not impair this process. In contrast, nuclear presence of WASp in TH2-skewed cells is small and its loss does not impair transcriptional reprogramming of GATA3 and IL4 promoters. Our study unveils an ARP2/3:VCA-independent function of nuclear-WASp in TH1-gene activation that is uncoupled from its cytoplasmic role in actin polymerization.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/s1937-6448(09)77005-4
发表时间：
2009
影响因子：
--
作者：
Meagher, Richard B.;Kandasamy, Muthugapatti K.;McKinney, Elizabeth C.;Roy, Eileen
通讯作者：
Roy, Eileen
影响因子：
14.8
作者：
Dahl, John Arne;Collas, Philippe
通讯作者：
Collas, Philippe
影响因子：
8.6
作者：
Adriani, Marsilio;Aoki, Joseph;Schwartzberg, Pamela L.
通讯作者：
Schwartzberg, Pamela L.
DOI：
10.4049/jimmunol.0804256
发表时间：
2009-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Astrakhan A;Ochs HD;Rawlings DJ
通讯作者：
Rawlings DJ