Modulation of STAT3 folding and function by TRiC/CCT chaperonin.
Modulation of STAT3 folding and function by TRiC/CCT chaperonin.
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DOI：
10.1371/journal.pbio.1001844
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发表时间：
2014-04
期刊：
影响因子：
9.8
通讯作者：
Tweardy DJ
中科院分区：
文献类型：
--
作者：
Kasembeli M;Lau WC;Roh SH;Eckols TK;Frydman J;Chiu W;Tweardy DJ
臭名昭著的癌症和炎症疾病相关信号分子Stat3的水平、折叠和功能通过与伴侣蛋白TRiC的相互作用受到调节；操纵这种相互作用是一种探索的治疗途径。转录信号转导因子3 （Signal transducer and activator of transcription, Stat3）将多种肽激素的信号从细胞表面传导到细胞核，并在许多类型的癌症中作为癌蛋白发挥作用，但人们对其如何在细胞内达到天然折叠状态知之甚少。在这里，我们发现Stat3是环状异质寡聚真核伴侣蛋白TRiC/CCT的一个新的底物，这有助于其在体外和体内的生物合成和活性。TRiC与Stat3的结合至少部分是由TRiC亚基CCT3介导的。Stat3与TRiC的结合主要定位于Stat3的富含β链的dna结合域。值得注意的是，通过在Stat3的n端从von Hippel-Lindau蛋白（vTBD）中设计一个额外的trc结合域来增强Stat3与TRiC的结合，进一步增加了Stat3对TRiC的亲和力及其功能，这是由Stat3与其磷酸化酪氨酸肽配体的结合能力决定的，这是Stat3激活的关键相互作用。因此，Stat3的水平和功能受TRiC调控，并可通过调控其与TRiC的相互作用来调节。Stat3是一种多结构域转录因子，通过将40多种肽激素的信号从细胞表面传递到细胞核，参与许多细胞功能。了解多结构域蛋白如何实现其完全折叠和功能状态具有重要的生物学意义。由于Stat3信号在许多病理条件下上调，包括癌症和炎症性疾病，因此深入了解控制其折叠的因素可能有助于识别可用于治疗的脆弱性。我们证明了真核细胞中主要的蛋白质折叠机器或伴侣蛋白TRiC/CCT是Stat3在合成过程中折叠和Stat3在细胞内充分发挥功能所必需的。我们还发现TRiC可以重新折叠化学变性的Stat3，并提供证据表明TRiC的CCT3亚基与Stat3的dna结合域结合。我们还发现Stat3的活性可以通过下调TRiC的水平而降低，并可以通过增加Stat3与TRiC的相互作用而增加。因此，TRiC调节Stat3蛋白水平及其功能，通过操纵其与TRiC的相互作用来调节Stat3，这是治疗癌症和炎症性疾病的潜在方法。
Levels, folding, and function of the infamous cancer and inflammatory disease-related signaling molecule Stat3 are regulated by interaction with the chaperonin TRiC; manipulation of this interaction is a therapeutic avenue for exploration. Signal transducer and activator of transcription 3 (Stat3) transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD), at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC. Stat3 is a multidomain transcription factor that contributes to many cellular functions by transmitting signals for over 40 peptide hormones from the cell surface to the nucleus. Understanding how multidomain proteins achieve their fully folded and functional state is of substantial biological interest. As Stat3 signaling is up-regulated in many pathological conditions, including cancer and inflammatory diseases, insight into what controls its folding may be useful for the identification of vulnerabilities that can be therapeutically exploited. We demonstrate that the major protein-folding machine or chaperonin within eukaryotic cells, TRiC/CCT, is required for Stat3 to fold during its synthesis and for Stat3 to be fully functional within the cell. We also find that TRiC can refold chemically denatured Stat3 and provide evidence that the CCT3 subunit of TRiC binds to the DNA-binding domain of Stat3. We also show that Stat3 activity is decreased by down-modulating levels of TRiC and can be increased by increasing Stat3's interaction with TRiC. TRiC therefore regulates both Stat3 protein levels and its function, making Stat3 modulation by manipulation of its interaction with TRiC a potential approach for the treatment of cancer and inflammatory diseases.
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影响因子：
3.7
作者：
Alten, Jeffrey A.;Moran, Ana;Tweardy, David J.
通讯作者：
Tweardy, David J.
影响因子：
10.5
作者：
Guenther, MG;Yu, JJ;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
11.4
作者：
FRYDMAN, J;NIMMESGERN, E;HARTL, FU
通讯作者：
HARTL, FU
影响因子：
5.3
作者：
GAO, YI;VAINBERG, IE;COWAN, NJ
通讯作者：
COWAN, NJ
影响因子：
5.3
作者：
Liu, XQ;Lin, CY;Erikson, RL
通讯作者：
Erikson, RL