Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex
Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex
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DOI：
10.1074/jbc.m105931200
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发表时间：
2001-12-07
影响因子：
4.8
通讯作者：
Voellmy, R
中科院分区：
文献类型：
--
作者：
Guo, YL;Guettouche, T;Voellmy, R
在没有应激的情况下，人热休克因子I（hHSF 1）处于其未活化形式。hHSF 1多肽与Hsp 90形成动态异源复合物，不能特异性结合DNA。当细胞受到应激时，异源复合物组装被破坏。未结合的hHSF 1同源三聚化，获得DNA结合活性，并集中在细胞核中，但保持转录失活。随后的反应将这种无活性的三聚体形式转化为活性的高度磷酸化的转录因子。在应激事件之后，hHSF 1被失活并最终返回到其未激活的形式。本文提供的证据表明，三聚体hHSF 1具有通过其调节结构域与Hsp 90-亲免疫素-p23复合物动态缔合的倾向。该异源复合物的形成导致三聚体hHSF 1的转录活性的抑制。应激变性蛋白质有效地与三聚体hHSF 1竞争Hsp 90-immunophilin-p23复合物，抵消异源复合物的组装和hHSF 1转录活性的抑制。这种抑制机制可能是对应激的成比例转录反应所必需的。异源复合物的形成也可能代表了使hHSF 1返回其未活化形式的第一步。
In the absence of stress, human heat shock factor I (hHSF1) is in its unactivated form. hHSF1 polypeptide is in a dynamic heterocomplex with Hsp90 and is incapable of specifically binding DNA. When cells are stressed, heterocomplex assembly is disrupted. Unbound hHSF1 homotrimerizes, acquires DNA binding activity, and concentrates in the nucleus, but remains transcriptionally inactive. A subsequent reaction converts this inactive, trimeric form into the active, hyperphosphorylated transcription factor. Subsequent to the stressful event, hHSF1 is deactivated and eventually returned to its unactivated form. Evidence is presented herein that trimeric hHSF1 has the propensity to dynamically associate with an Hsp90-immunophilin-p23 complex through its regulatory domain. Formation of this heterocomplex results in repression of the transcriptional activity of trimeric hHSF1. Stress-denatured proteins effectively compete with trimeric hHSF1 for Hsp90-immunophilin-p23 complex, counteracting assembly of the heterocomplex and repression of hHSF1 transcriptional activity. This repression mechanism may be required for a proportional transcriptional response to stress. Formation of the heterocomplex may also represent the first step toward returning the hHSF1 to its unactivated form.