Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1.
Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1.
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DOI：
10.1371/journal.pbio.1000060
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发表时间：
2009-03-03
期刊：
影响因子：
9.8
通讯作者：
Ashrafi K
中科院分区：
文献类型：
--
作者：
Jones KT;Greer ER;Pearce D;Ashrafi K
雷帕霉素（TOR）激酶的靶点协调调节基本代谢和细胞过程以支持生长、增殖、存活和分化，因此其已被提议作为治疗癌症、代谢疾病和衰老的治疗靶点。TOR激酶存在于两种生物化学和功能不同的复合物中，称为TORC 1和TORC 2。借助于特异性抑制TORC 1的化合物雷帕霉素，TORC 1在调节翻译和细胞生长中的作用已被广泛研究。由于缺乏药理学抑制剂及其在哺乳动物中的遗传致死性，TORC 2的生理作用在很大程度上仍然难以捉摸。在TORC 2的潜在靶点中，促存活激酶AKT引起了广泛关注。然而，在完整动物的背景下，TORC 2磷酸化AKT的生理后果仍然知之甚少。在这里，我们描述了可行的功能丧失突变体的秀丽隐杆线虫同源的TORC 2特异性组件，Rictor（CeRictor）。这些突变体表现出轻微的发育迟缓和减小的体型，但增加了脂质储存。CeRictor的这些功能不是通过调节AKT激酶或其主要下游靶点（胰岛素调节的FOXO转录因子β 16）介导的。我们发现，sgk-1（血清和糖皮质激素诱导的激酶的同源物）的缺失模拟了CeRictor突变体的发育、生长和代谢表型，而sgk-1中的一种新的功能获得性突变抑制了这些表型，表明SGK-1是CeRictor活性的介体。这些发现确定了由SGK介导的TORC 2在C.他们的研究表明，AKT是TORC 2功能的主要效应子。雷帕霉素（TOR）激酶的靶点作为能量状态的保守传感器，并通过两个独立的多蛋白复合物控制多种功能，如代谢、生长和细胞大小。对免疫抑制药物雷帕霉素敏感的TOR复合物1（TORC 1）已被充分理解，但第二种TOR复合物（TORC 2）的生理作用和分子作用机制尚不清楚。我们描述的突变体在单一的秀丽隐杆线虫同源基因Rictor，这是定义组成部分的TORC 2信号复合物。变异蠕虫体积小，发育迟缓，繁殖力降低，比野生型C储存更多的脂肪。elegans做的。Akt激酶是介导胰岛素和其他生长因子作用的促存活激酶，被认为是TORC 2信号传导的关键介质，因为它们是TORC 2磷酸化的靶标。我们发现，然而，在C。在线虫中，TORC 2调节脂肪储存、大小和发育，完全独立于Akt激酶和胰岛素信号传导的主要靶点FOXO家族转录因子β-16。相反，我们在遗传学上表明，TORC 2通过激活SGK-1（一种与Akt密切相关的激酶）来控制所有三种表型。这项工作表明了TORC 2在脂肪调节中的作用，并表明SGK-1是TORC 2信号传导的生理学重要介质。 C.线虫TOR复合物2通过下游SGK-1激酶的激活调节脂质储存、身体大小和发育，而不依赖于AKT激酶和foxo-16/FOXO转录因子。
The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of cancer, metabolic disease, and aging. The TOR kinase is found in two biochemically and functionally distinct complexes, termed TORC1 and TORC2. Aided by the compound rapamycin, which specifically inhibits TORC1, the role of TORC1 in regulating translation and cellular growth has been extensively studied. The physiological roles of TORC2 have remained largely elusive due to the lack of pharmacological inhibitors and its genetic lethality in mammals. Among potential targets of TORC2, the pro-survival kinase AKT has garnered much attention. Within the context of intact animals, however, the physiological consequences of phosphorylation of AKT by TORC2 remain poorly understood. Here we describe viable loss-of-function mutants in the Caenorhabditis elegans homolog of the TORC2-specific component, Rictor (CeRictor). These mutants display a mild developmental delay and decreased body size, but have increased lipid storage. These functions of CeRictor are not mediated through the regulation of AKT kinases or their major downstream target, the insulin-regulated FOXO transcription factor DAF-16. We found that loss of sgk-1, a homolog of the serum- and glucocorticoid-induced kinase, mimics the developmental, growth, and metabolic phenotypes of CeRictor mutants, while a novel, gain-of-function mutation in sgk-1 suppresses these phenotypes, indicating that SGK-1 is a mediator of CeRictor activity. These findings identify new physiological roles for TORC2, mediated by SGK, in regulation of C. elegans lipid accumulation and growth, and they challenge the notion that AKT is the primary effector of TORC2 function. The target of rapamycin (TOR) kinase acts as a conserved sensor of energy status and governs diverse functions such as metabolism, growth, and cell size via two separate multiprotein complexes. TOR complex 1 (TORC1), which is sensitive to the immunosuppressant drug rapamycin, is well understood but the physiological roles and molecular mechanisms of action of the second TOR complex (TORC2) are not so clear. We describe mutants in the single Caenorhabditis elegans homolog of the gene Rictor, which is the defining component of the TORC2 signaling complex. Mutant worms are small, developmentally delayed, have reduced fecundity, and store more fat than wild-type C. elegans does. Akt kinases, which are pro-survival kinases that mediate the effects of insulin and other growth factors, have been postulated to be key mediators of TORC2 signaling, as they are targets of TORC2 phosphorylation. We find, however, that in C. elegans, TORC2 regulates fat storage, size, and development entirely independent of the Akt kinases and of the major target of insulin signaling, the FOXO-family transcription factor DAF-16. Instead, we show genetically that TORC2 acts through the activation of SGK-1, a kinase closely related to Akt, to govern all three phenotypes. This work indicates a role for TORC2 in fat regulation and shows that SGK-1 is a physiologically significant mediator of TORC2 signaling. C. elegans TOR complex 2 regulates lipid storage, body size, and development through downstream activation of the SGK-1 kinase, independent of AKT kinases and of the DAF-16/FOXO transcription factor.
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