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PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.

ABSTRACT: Protein synthesis is a key regulated cellular process that links nutrient availability and organismal growth. It has long been known that some cellular proteins continue to be synthesized under conditions where global translation is severely compromised. One prominent example is the selective translation of heat shock proteins (Hsps) under stress conditions. Although the transcriptional regulation of Hsp genes has been well established, neither the specific translation-promoting features nor the regulatory mechanism of the translation machinery have been clearly defined. Here we show that the stress-induced preferential translation of Hsp70 mRNA is negatively regulated by PI3K-mTORC1 signaling. Despite the transcriptional up-regulation, the translation of Hsp70 mRNA is deficient in cells lacking tuberous sclerosis complex 2. Conversely, Hsp70 synthesis is enhanced under the reduced PI3K-mTORC1 signaling. We found that the 5' UTR of Hsp70 mRNA contributes to cap-independent translation without exhibiting typical features of internal ribosome entry site. Our findings imply a plausible mechanism for how persistent PI3K-mTORC1 signaling favors the development of age-related pathologies by attenuating stress resistance.

SUBMITTER: Sun J

PROVIDER: S-EPMC3057780 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.

Sun Jun J Conn Crystal S CS Han Yan Y Yeung Vincent V Qian Shu-Bing SB

The Journal of biological chemistry 20101222 8

Protein synthesis is a key regulated cellular process that links nutrient availability and organismal growth. It has long been known that some cellular proteins continue to be synthesized under conditions where global translation is severely compromised. One prominent example is the selective translation of heat shock proteins (Hsps) under stress conditions. Although the transcriptional regulation of Hsp genes has been well established, neither the specific translation-promoting features nor the ...[more]

PMID: 21177857

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Project description:Background and Aim: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a crucial role in autophagy and inflammation. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic and anti-inflammatory effects in mice. However, its effects on autophagy and the PI3K/Akt/mTORC1 signaling pathway remain unclear. This study aimed to explore the effects of SYDC on autophagy and PI3K/Akt/mTORC1 signaling in the apolipoprotein E knockout (ApoE-/-) mouse model and in macrophage-derived foam cells to delineate the underlying mechanism. Methods: After 6 weeks of high-fat diet, ApoE-/- mice were randomly grouped into control, Lipitor, low-SYDC (SYDC-L), middle-SYDC (SYDC-M), and high-SYDC (SYDC-H) groups (n = 10). The mice were intragastrically administered the respective treatment for 6 weeks. Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (80?µg/ml) for 24 h and then pretreated with SYDC freeze-dried powder for another 24 h. Cells treated with SYDC were co-cultured for 24 h with LY294002, tricirbine, and rapamycin to investigate the effects on the PI3K/Akt/mTORC1 signaling pathway. Results: SYDC ameliorated blood lipid levels, reduced the atherosclerotic index and plaque areas in the aortic root in mice, and inhibited total cholesterol (TC) levels and cholinesterase (ChE)/TC ratios in ox-LDL stimulated macrophages. Moreover, SYDC up-regulated Beclin1 and LC3II/I proteins in mice and in the ox-LDL-stimulated macrophages. Moreover, SYDC inhibited AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 in mice and in ox-LDL-stimulated macrophages. Furthermore, SYDC's inhibitory of ChE/TC ratios in ox-LDL-stimulated macrophages was not changed by selective inhibition of the PI3K/Akt/mTORC1 pathway. Conclusions: Our results highlight that SYDC treatment attenuates foam cell formation by promoting autophagy via inhibiting activation of the PI3K/Akt/mTORC1 signaling pathway. This study provides new insights into the molecular mechanism underlying SYDC's therapeutic potential for treating atherosclerosis.

Dataset Information

PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.

Publications

PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.

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