C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.
C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.
复制标题
DOI：
10.1371/journal.pgen.1002948
复制
发表时间：
2012-09
期刊：
影响因子：
4.5
通讯作者：
Hsu AL
中科院分区：
文献类型：
--
作者：
Chiang WC;Tishkoff DX;Yang B;Wilson-Grady J;Yu X;Mazer T;Eckersdorff M;Gygi SP;Lombard DB;Hsu AL
FoxO转录因子和sirtuin家族脱乙酰基酶调节多种生物过程，包括应激反应和寿命。在这里，我们表明，秀丽隐杆线虫sirtuin SIR-2.4-同源的哺乳动物SIRT 6和SIRT 7蛋白质，促进依赖转录和应激诱导的转录-16核定位。SIR-2.4是抵抗多种应激源所必需的：热休克、氧化损伤和蛋白毒性。相比之下，SIR-2.4在很大程度上与β-16核定位有关，并且响应于减少的胰岛素/IGF-1样信号传导而发挥功能。虽然已知乙酰化调节哺乳动物FoxO蛋白的定位和活性，但这种修饰以前没有在B16上描述过。我们发现在sir-2.4突变体中α-16是高度乙酰化的。相反，cbp-16被乙酰基转移酶CBP-1乙酰化，cbp-16被低乙酰化，并在cbp-1抑制作用下组成性核化。令人惊讶的是，SIR-2.4催化突变体有效地挽救了sir-2.4无效动物中的p16定位缺陷。野生型或突变型SIR-2.4均可抑制CBP-1体外对CYP-16的乙酰化，表明SIR-2.4通过阻止CBP-1介导的应激条件下乙酰化间接调节CYP-16的乙酰化。两者合计，我们的研究结果确定SIR-2.4作为一个关键的调节剂，特别是在压力反应的背景下，α-16。此外，他们揭示了一种新的作用，乙酰化，调节CBP-1和SIR-2.4的拮抗活性，在调节α-16的定位和功能。感知和适当地应对环境的侮辱是所有生物面临的挑战。在蛔虫C.在线虫中，FoxO蛋白16在应激反应中移动到细胞核，在那里它调节基因表达，并在确保生物体生存方面发挥关键作用。在这篇手稿中，我们将SIR-2.4描述为一种在应激过程中促进β-16功能的新因子。SIR-2.4是一个名为sirtuins的蛋白质家族的成员，其中一些蛋白质可以促进模型生物的寿命延长。缺乏SIR-2.4的蠕虫表现出对多种应激源的应答中受损的N16核募集、N16依赖性基因表达和存活。SIR-2.4通过间接影响β-16上称为乙酰化的修饰水平来调节β-16。总体而言，我们的工作揭示了SIR-2.4是C.优美的未来的研究将解决哺乳动物SIR-2.4同源物SIRT 6和SIRT 7是否对哺乳动物FoxO蛋白具有相似的作用。
FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4—homolog of mammalian SIRT6 and SIRT7 proteins—promotes DAF-16–dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function. Sensing and responding appropriately to environmental insults is a challenge facing all organisms. In the roundworm C. elegans, the FoxO protein DAF-16 moves to the nucleus in response to stress, where it regulates gene expression and plays a key role in ensuring organismal survival. In this manuscript, we characterize SIR-2.4 as a novel factor that promotes DAF-16 function during stress. SIR-2.4 is a member of a family of proteins called sirtuins, some of which promote increased lifespan in model organisms. Worms lacking SIR-2.4 show impaired DAF-16 nuclear recruitment, DAF-16–dependent gene expression, and survival in response to a variety of stressors. SIR-2.4 regulates DAF-16 by indirectly affecting levels of a modification called acetylation on DAF-16. Overall, our work has revealed SIR-2.4 to be a key new factor in stress resistance and DAF-16 regulation in C. elegans. Future studies will address whether mammalian SIR-2.4 homologs SIRT6 and SIRT7 act similarly towards mammalian FoxO proteins.
登录
查看更多内容
影响因子：
64.8
作者：
Burnett, Camilla;Valentini, Sara;Cabreiro, Filipe;Goss, Martin;Somogyvari, Milan;Piper, Matthew D.;Hoddinott, Matthew;Sutphin, George L.;Leko, Vid;McElwee, Joshua J.;Vazquez-Manrique, Rafael P.;Orfila, Anne-Marie;Ackerman, Daniel;Au, Catherine;Vinti, Giovanna;Riesen, Michele;Howard, Ken;Neri, Christian;Bedalov, Antonio;Kaeberlein, Matt;Soti, Csaba;Partridge, Linda;Gems, David
通讯作者：
Gems, David
影响因子：
29
作者：
Jing, Enxuan;Gesta, Stephane;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
影响因子：
5.3
作者：
Eastburn, DJ;Han, M
通讯作者：
Han, M
影响因子：
56.9
作者：
Lee, SS;Kennedy, S;Ruvkun, G
通讯作者：
Ruvkun, G