Non-genomic STAT5-dependent effects at the endoplasmic reticulum and Golgi apparatus and STAT6-GFP in mitochondria.
Non-genomic STAT5-dependent effects at the endoplasmic reticulum and Golgi apparatus and STAT6-GFP in mitochondria.
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DOI：
10.4161/jkst.24860
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发表时间：
2013-10-01
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影响因子：
--
通讯作者：
Sehgal PB
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作者：
Sehgal PB
STAT蛋白是众所周知的调节核基因表达的转录因子。最近的新研究表明，STAT5A/B和STAT6具有新的非基因组功能。在人的肺动脉内皮细胞中，STAT5A包括STAT5A-GFP与高尔基体结合，STAT5A和B与内质网结合。急性siRNA介导的STAT5A/B基因敲除导致内质网(ER)迅速发生囊性变化，其特征是内质网结构蛋白网状4(RTN4；也称为Nogo-B)和内质网驻留的GTP酶atlastin-3(ATL3)沿囊膜和囊区边界沉积，并伴有高尔基碎裂。功能后果包括顺行运输减少，内质网应激反应(GRP78/Bip增加)和最终线粒体碎裂。这种表型是“非基因组”的，因为它是在去核的细胞质中诱导出来的。在交叉免疫分析中，与ATL3和内质网管腔间隔区CLIMP63(也称为细胞骨架相关蛋白4，CKAP4)相关的STAT5A和B物种，而不是RTN4。从疾病意义的角度来看，我们假设STAT5，已知受雌二醇-17β和催乳素的影响，代表了特发性肺动脉高压(IPAH)发病机制中对性别敏感的决定因素，这种疾病包括ER/高尔基体功能障碍，但在青春期后女性中的患病率高出2-4倍。最近的另一项研究提供了证据表明，在活细胞、免疫荧光和免疫电子显微镜中，STAT6-GFP，但不是STAT3-GFP、STAT3-DsRed或STAT3-Flag与线粒体有关。STAT6-GFP(1-459)的N端截短，缺失SH2结构域和酪氨酸磷酸化位点，与线粒体密切相关。因此，新出现的生物状态蛋白包括在结构和功能上的非基因组作用，在由内质网、高尔基体和线粒体组成的三个密切相关的膜细胞器中。
STAT protein species are well-known as transcription factors that regulate nuclear gene expression. Recent novel lines of research suggest new non-genomic functions of STAT5A/B and STAT6. It was discovered in human pulmonary arterial endothelial cells that STAT5A, including STAT5A-GFP, constitutively associated with the Golgi apparatus, and both STAT5A and B with the endoplasmic reticulum. Acute siRNA-mediated knockdown of STAT5A/B led to the rapid development of a dramatic cystic change in the endoplasmic reticulum (ER) characterized by deposition of the ER structural protein reticulon-4 (RTN4; also called Nogo-B) and the ER-resident GTPase atlastin-3 (ATL3) along cyst membranes and cyst-zone boundaries, accompanied by Golgi fragmentation. Functional consequences included reduced anterograde trafficking, an ER stress response (increased GRP78/BiP) and eventual mitochondrial fragmentation. This phenotype was “non-genomic” in that it was elicited in enucleated cytoplasts. In cross-immunopanning assays STAT5A and B species associated with ATL3, and the ER-lumen spacer CLIMP63 (also called cytoskeleton-associated protein 4, CKAP4) but not RTN4. From a disease significance perspective we posit that STAT5, which is known to be affected by estradiol-17β and prolactin, represents the gender-sensitive determinant in the pathogenesis of idiopathic pulmonary hypertension (IPAH), a disease which includes ER/Golgi dysfunctions but with a 2- to 4-fold higher prevalence in postpubertal women. A separate line of recent research produced evidence for the association of STAT6-GFP, but not STAT3-GFP, STAT3-DsRed, or STAT3-Flag, with mitochondria in live-cell, immunofluorescence, and immunoelectron microscopy. An N-terminal truncation of STAT6-GFP (1–459), which lacked the SH2 domain and Tyr-phosphorylation site, constitutively associated with mitochondria. Thus, the emergent new of biology STAT proteins includes non-genomic roles—structurally and functionally—in the three closely related membrane organelles consisting of the endoplasmic reticulum, Golgi apparatus, and mitochondria.