The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans.
The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1007038
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发表时间：
2017-10
期刊：
影响因子：
4.5
通讯作者：
Samuelson AV
中科院分区：
文献类型：
--
作者：
Das R;Melo JA;Thondamal M;Morton EA;Cornwell AB;Crick B;Kim JH;Swartz EW;Lamitina T;Douglas PM;Samuelson AV
一个由分子伴侣和蛋白质清除机制组成的广泛的蛋白质恒定网络共同发挥功能，以保持蛋白质组的完整性和弹性。这种网络的有效性随着年龄的增长而恶化，这与许多临床表现相吻合，包括神经系统的蛋白质聚集性疾病。蛋白稳定性的下降可以通过激活细胞保护性转录反应来延缓，细胞保护性转录反应对环境应激以及内部代谢和生理信号敏感。同源域相互作用蛋白激酶(HIPK)家族成员是一类保守的转录辅助因子，参与了酵母对哺乳动物的遗传毒性和代谢应激反应。我们证明了唯一的秀丽线虫Hipk同源物HPK-1的结构性表达足以延缓衰老，保持蛋白稳定，并提高抗逆性，而HPK-1的缺失对这些表型是有害的。我们发现，HPK-1通过由热休克转录因子(HSF-1)和雷帕霉素复合体1(TORC1)定义的不同但互补的遗传途径来维持蛋白稳定和延长寿命。我们证明了HPK-1拮抗HSF-1的和甲基化，这是一种与哺乳动物转录活性降低相关的翻译后修饰。我们表明，RNAi抑制苏莫化增强了热休克反应中依赖于HSF-1的伴侣蛋白的转录诱导。我们发现HSF-1需要HPK-1在热应激后诱导分子伴侣，从而延长寿命。我们还表明，HPK-1与HSF-1在没有热应激的情况下维持蛋白稳定是必需的，从而防止形成聚谷氨酰胺(Q35：：YFP)蛋白聚集体和相关的运动性毒性。一旦动物达到生殖成熟，HPK-1/HSF-1的这些功能就会迅速下调。我们证明，HPK-1通过另一个独立的机制：诱导自噬，加强蛋白稳定并延长寿命。HPK-1是诱导自噬小体形成和自噬基因表达所必需的，以响应饮食限制(DR)或TORC1的失活。自噬刺激转录因子PHA-4/FoxA和MXL-2/MLX，而不是hlh-30/TFEB或核激素受体NHR-62，是由于HPK-1过表达而延长寿命所必需的。HPK-1的表达本身是由营养应激后的转录机制和热应激反应的转录后机制诱导的。总体而言，我们的结果将HPK-1定位在更大的蛋白抑制网络上游的中央调控节点，通过伴侣表达促进蛋白质折叠在转录水平发挥作用，通过自噬基因表达促进蛋白质周转。因此，HPK-1为以蛋白质稳态系统为靶点的药物提供了一个有希望的干预点，以此作为保持健壮长寿的一种手段。衰老是活力的渐进性衰退。衰老的一个标志是通常保持细胞和组织的健壮性和弹性的保护机制的衰退。蛋白质平衡是一个专门用于促进蛋白质组稳定性的机制，蛋白质组是细胞通过伴侣辅助折叠和错误折叠或外来蛋白质的降解相结合而产生的多肽的集合。我们已经在线虫中发现了HPK-1(编码一个同源结构域相互作用的蛋白激酶)，它是蛋白质平衡机制中一个重要的转录调控成分。HPK-1通过两种不同的机制促进蛋白稳定：第一，通过热休克转录因子(HSF-1)刺激伴侣基因的表达；第二，刺激自噬基因的表达，而不是雷帕霉素(TOR)信号通路的靶标。因此，HPK-1为干预提供了一个有吸引力的靶点，通过保护蛋白质组的整体健康来保持衰老期间的生理弹性。
An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues. The homeodomain-interacting protein kinase (hipk) family members are conserved transcriptional co-factors that have been implicated in both genotoxic and metabolic stress responses from yeast to mammals. We demonstrate that constitutive expression of the sole Caenorhabditis elegans Hipk homolog, hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 is deleterious to these phenotypes. We show that HPK-1 preserves proteostasis and extends longevity through distinct but complementary genetic pathways defined by the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). We demonstrate that HPK-1 antagonizes sumoylation of HSF-1, a post-translational modification associated with reduced transcriptional activity in mammals. We show that inhibition of sumoylation by RNAi enhances HSF-1-dependent transcriptional induction of chaperones in response to heat shock. We find that hpk-1 is required for HSF-1 to induce molecular chaperones after thermal stress and enhances hormetic extension of longevity. We also show that HPK-1 is required in conjunction with HSF-1 for maintenance of proteostasis in the absence of thermal stress, protecting against the formation of polyglutamine (Q35::YFP) protein aggregates and associated locomotory toxicity. These functions of HPK-1/HSF-1 undergo rapid down-regulation once animals reach reproductive maturity. We show that HPK-1 fortifies proteostasis and extends longevity by an additional independent mechanism: induction of autophagy. HPK-1 is necessary for induction of autophagosome formation and autophagy gene expression in response to dietary restriction (DR) or inactivation of TORC1. The autophagy-stimulating transcription factors pha-4/FoxA and mxl-2/Mlx, but not hlh-30/TFEB or the nuclear hormone receptor nhr-62, are necessary for extended longevity resulting from HPK-1 overexpression. HPK-1 expression is itself induced by transcriptional mechanisms after nutritional stress, and post-transcriptional mechanisms in response to thermal stress. Collectively our results position HPK-1 at a central regulatory node upstream of the greater proteostatic network, acting at the transcriptional level by promoting protein folding via chaperone expression, and protein turnover via expression of autophagy genes. HPK-1 therefore provides a promising intervention point for pharmacological agents targeting the protein homeostasis system as a means of preserving robust longevity. Aging is the gradual and progressive decline of vitality. A hallmark of aging is the decay of protective mechanisms that normally preserve the robustness and resiliency of cells and tissues. Proteostasis is the term that applies specifically to those mechanisms that promote stability of the proteome, the collection of polypeptides that cells produce, by a combination of chaperone-assisted folding and degradation of misfolded or extraneous proteins. We have identified hpk-1 (encoding a homeodomain-interacting protein kinase) in the nematode C. elegans as an important transcriptional regulatory component of the proteostasis machinery. HPK-1 promotes proteostasis by linking two distinct mechanisms: first by stimulating chaperone gene expression via the heat shock transcription factor (HSF-1), and second by stimulating autophagy gene expression in opposition to the target of rapamycin (TOR) kinase signaling pathway. HPK-1 therefore provides an attractive target for interventions to preserve physiological resiliency during aging by preserving the overall health of the proteome.
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影响因子：
12.4
作者：
Conrad E;Polonio-Vallon T;Meister M;Matt S;Bitomsky N;Herbel C;Liebl M;Greiner V;Kriznik B;Schumacher S;Krieghoff-Henning E;Hofmann TG
通讯作者：
Hofmann TG
影响因子：
2.5
作者：
Berber, Slavica;Llamosas, Estelle;Nicholas, Hannah R.
通讯作者：
Nicholas, Hannah R.
影响因子：
4.5
作者：
Gelino S;Chang JT;Kumsta C;She X;Davis A;Nguyen C;Panowski S;Hansen M
通讯作者：
Hansen M
影响因子：
64.5
作者：
Durieux J;Wolff S;Dillin A
通讯作者：
Dillin A
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y