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TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors
Canrong Li1, Yuguo Yi1, Yingyi Ouyang1
1School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China.
Background:
Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking.
Results:
We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1.
Conclusions:
TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.
Insights
Scientists developed TORSEL, a novel sensor to monitor mechanistic target of rapamycin complex 1 (mTORC1) activity in real-time. This tool aids in discovering new mTORC1 inhibitors for diseases like cancer and neurodegeneration.
Area of Science:
- Cellular signaling
- Molecular biology
- Biochemistry
Background:
- Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator implicated in cancer, diabetes, aging, and neurodegeneration.
- A critical need exists for efficient tools to monitor mTORC1 inhibition in live cells and tissues.
Purpose of the Study:
- To develop a genetically encoded sensor for real-time monitoring of mTORC1 activity.
- To validate the sensor's efficacy in detecting various forms of mTORC1 inhibition.
- To utilize the sensor for screening and identifying novel mTORC1 inhibitors.
Main Methods:
- Development of a genetically encoded sensor, TORSEL, based on 4EBP1 dephosphorylation and eIF4E interaction.
- Utilizing TORSEL for imaging-based visual screening in living cells and tissues.
- Pharmacological and genetic validation of TORSEL's specificity for mTORC1 inhibition.
Main Results:
- TORSEL exhibits a distinct fluorescence shift from diffuse to punctate upon mTORC1 inhibition.
- The sensor accurately detects physiological, pharmacological, and genetic inhibition of mTORC1 signaling.
- TORSEL facilitated the identification of histone deacetylase inhibitors that selectively target nutrient-sensing pathways to inhibit mTORC1.
Conclusions:
- TORSEL serves as a unique and efficient living cell sensor for detecting mTORC1 activity.
- Histone deacetylase inhibitors, including panobinostat, were identified as agents that target mTORC1 signaling via amino acid sensing pathways.
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