Elucidation of an mTORC2-PKC-NRF2 pathway that sustains the ATF4 stress response and identification of Sirt5 as a key ATF4 effector.
Elucidation of an mTORC2-PKC-NRF2 pathway that sustains the ATF4 stress response and identification of Sirt5 as a key ATF4 effector.
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DOI：
10.1038/s41420-022-01156-5
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发表时间：
2022-08-13
影响因子：
7
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
--
作者：
Li, Ruizhi;Wilson, Kristin F.;Cerione, Richard A.
增殖中的癌细胞在受到由活性氧、缺氧、营养缺乏和基质脱落引起的氧化应激的挑战时，依靠谷氨酰胺代谢生存。ATF4是一种关键的应激反应转录因子，对于癌细胞在这些不同类型的应激条件下维持谷氨酰胺代谢是必不可少的。虽然ATF4转录本是如何被翻译成蛋白质作为应激反应的，但一个重要的问题涉及如何维持ATF4的信息水平，使癌细胞能够在营养缺乏和破坏活性氧的挑战中生存下来。在这里，我们现在确定了在三阴性乳腺癌细胞中提供持续的ATF4反应并使它们在遇到这些挑战时能够存活的途径。这一信号通路始于mTORC2，mTORC2在感受到谷氨酰胺缺乏或谷氨酰胺代谢急性抑制引起的细胞应激时，启动一系列事件，触发ATF4转录的增加。令人惊讶的是，这个信号通路并不依赖于AKT的激活，而是需要mTORC2的靶标PKC，它激活转录因子Nrf2，然后诱导ATF4的表达。此外，我们确定了sirtuin家族成员，NAD+依赖的去琥珀酸酶SIRT5，作为ATF4的关键转录靶点，在代谢应激期间促进癌细胞存活。SIRT5通过调节各种酶的活性和保护谷氨酰胺分解所必需的酶谷氨酰胺酶C(GAC)不被降解，在支持癌细胞新陈代谢方面发挥着重要作用。我们证明，在谷氨酰胺剥夺诱导的压力下，SIRT5的异位表达可以补偿暴露在谷氨酰胺剥夺诱导的压力下的细胞ATF4的下调。这些发现对导致ATF4持续表达作为应激诱导的谷氨酰胺代谢调节因子的信号通路提供了重要的新见解，并突出了SIRT5作为ATF4对代谢应激反应的重要效应因子。
Proliferating cancer cells are dependent on glutamine metabolism for survival when challenged with oxidative stresses caused by reactive oxygen species, hypoxia, nutrient deprivation and matrix detachment. ATF4, a key stress responsive transcription factor, is essential for cancer cells to sustain glutamine metabolism when challenged with these various types of stress. While it is well documented how the ATF4 transcript is translated into protein as a stress response, an important question concerns how the ATF4 message levels are sustained to enable cancer cells to survive the challenges of nutrient deprivation and damaging reactive oxygen species. Here, we now identify the pathway in triple negative breast cancer cells that provides a sustained ATF4 response and enables their survival when encountering these challenges. This signaling pathway starts with mTORC2, which upon sensing cellular stresses arising from glutamine deprivation or an acute inhibition of glutamine metabolism, initiates a cascade of events that triggers an increase in ATF4 transcription. Surprisingly, this signaling pathway is not dependent on AKT activation, but rather requires the mTORC2 target, PKC, which activates the transcription factor Nrf2 that then induces ATF4 expression. Additionally, we identify a sirtuin family member, the NAD+-dependent de-succinylase Sirt5, as a key transcriptional target for ATF4 that promotes cancer cell survival during metabolic stress. Sirt5 plays fundamental roles in supporting cancer cell metabolism by regulating various enzymatic activities and by protecting an enzyme essential for glutaminolysis, glutaminase C (GAC), from degradation. We demonstrate that ectopic expression of Sirt5 compensates for knockdowns of ATF4 in cells exposed to glutamine deprivation-induced stress. These findings provide important new insights into the signaling cues that lead to sustained ATF4 expression as a general stress-induced regulator of glutamine metabolism, as well as highlight Sirt5 an essential effector of the ATF4 response to metabolic stress.
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影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
影响因子：
5.7
作者：
Kitamura H;Motohashi H
通讯作者：
Motohashi H
影响因子：
8.8
作者：
Miyo M;Yamamoto H;Konno M;Colvin H;Nishida N;Koseki J;Kawamoto K;Ogawa H;Hamabe A;Uemura M;Nishimura J;Hata T;Takemasa I;Mizushima T;Doki Y;Mori M;Ishii H
通讯作者：
Ishii H
CRIF1 共激活 PKC-delta 通过磷酸化 NRF2 Ser40 调节照射后骨髓多能间充质基质细胞中的氧化应激。
影响因子：
12.4
作者：
Chen L;Ran Q;Xiang Y;Xiang L;Chen L;Li F;Wu J;Wu C;Li Z
通讯作者：
Li Z
DOI：
10.1073/pnas.1911954116
发表时间：
2019-12-26
影响因子：
11.1
作者：
Greene, Kai Su;Lukey, Michael J.;Cerione, Richard A.
通讯作者：
Cerione, Richard A.