Heat shock transcription factor 1 is activated as a consequence of lymphocyte activation and regulates a major proteostasis network in T cells critical for cell division during stress.
Heat shock transcription factor 1 is activated as a consequence of lymphocyte activation and regulates a major proteostasis network in T cells critical for cell division during stress.
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DOI：
10.4049/jimmunol.1202831
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发表时间：
2013-10-15
期刊：
影响因子：
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通讯作者：
Woodward JG
中科院分区：
文献类型：
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作者：
Gandhapudi SK;Murapa P;Threlkeld ZD;Ward M;Sarge KD;Snow C;Woodward JG
热休克转录因子1（HSF 1）是真核细胞热休克反应的主要转录调节因子。HSF 1还响应于多种细胞应激源而被诱发，包括升高的温度、氧化应激和其他蛋白毒性应激源。先前，我们证明了HSF 1在发热范围温度（39.5°C）下在初始T细胞中被激活，并且在发热温度下对体外T细胞增殖至关重要。在这项研究中，我们证明，小鼠HSF 1成为激活的DNA结合形式和反式激活淋巴细胞中的大量基因严格作为受体激活的结果，在没有明显的细胞应激。比较在37°C下活化的T细胞中HSF 1 +/+和HSF 1 −/−基因表达的微阵列分析揭示了在非应激T细胞中由HSF 1显著调节的323个基因的多样性。体内增殖研究显示，在模拟强免疫应答的条件下（葡萄球菌肠毒素B诱导T细胞活化），HSF 1 −/− T细胞扩增显著受损。即使在非发热温度下也观察到由于HSF 1的损失而导致的这种增殖缺陷。在发烧温度下激活的HSF 1-/-T细胞显示细胞周期中细胞周期蛋白E和细胞周期蛋白A蛋白的急剧减少，尽管这些基因的转录不受影响。最后，来自HSF 1-/-小鼠而非HSF 1 +/+小鼠的B细胞和造血干细胞增殖也在应激条件下减弱，表明HSF 1对应激条件下活化的淋巴细胞的细胞周期进展至关重要。
Heat Shock Transcription Factor 1 (HSF1) is a major transcriptional regulator of the heat shock response in eukaryotic cells. HSF1 is also evoked in response to a variety of cellular stressors including elevated temperatures, oxidative stress, and other proteotoxic stressors. Previously, we demonstrated that HSF1 is activated in naive T cells at fever range temperatures (39.5°C) and is critical for in vitro T cell proliferation at fever temperatures. In this study, we demonstrated thatmurine HSF1 became activated to the DNA-binding form and trans-activated a large number of genes in lymphoid cells strictly as a consequence of receptor activation in the absence of apparent cellular stress. Microarray analysis comparing HSF1+/+ and HSF1−/− gene expression in T cells activated at 37°C revealed a diverse set of 323 genes significantly regulated by HSF1 in non-stressed T cells. In vivo proliferation studies revealed a significant impairment of HSF1−/− T cell expansion under conditions mimicking a robust immune response (staphylococcal enterotoxin B induced T cell activation). This proliferation defect due to loss of HSF1 is observed even under non-febrile temperatures. HSF1−/− T cells activated at fever temperatures show a dramatic reduction in cyclin E and cyclin A proteins during the cell cycle, although the transcription of these genes was not affected. Finally, B cell, and hematopoietic stem cell proliferation from HSF1−/− mice, but not HSF1+/+ mice were also attenuated under stressful conditions, indicating that HSF1 is critical for the cell cycle progression of lymphoid cells activated under stressful conditions.