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Published on: February 14, 2016
Mislocalization of TORC1 to Lysosomes Caused by KIF11 Inhibition Leads to Aberrant TORC1 Activity
Yoon-Gu Jang1,2, Yujin Choi1,2, Kyoungho Jun1,2
1Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea.
Abstract:
While the growth factors like insulin initiate a signaling cascade to induce conformational changes in the mechanistic target of rapamycin complex 1 (mTORC1), amino acids cause the complex to localize to the site of activation, the lysosome. The precise mechanism of how mTORC1 moves in and out of the lysosome is yet to be elucidated in detail. Here we report that microtubules and the motor protein KIF11 are required for the proper dissociation of mTORC1 from the lysosome upon amino acid scarcity. When microtubules are disrupted or KIF11 is knocked down, we observe that mTORC1 localizes to the lysosome even in the amino acid-starved situation where it should be dispersed in the cytosol, causing an elevated mTORC1 activity. Moreover, in the mechanistic perspective, we discover that mTORC1 interacts with KIF11 on the motor domain of KIF11, enabling the complex to move out of the lysosome along microtubules. Our results suggest not only a novel way of the regulation regarding amino acid availability for mTORC1, but also a new role of KIF11 and microtubules in mTOR signaling.
Insights
Microtubules and KIF11 motor protein control mTORC1
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Insulin and amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) signaling.
- Amino acids induce mTORC1 localization to the lysosome for activation.
- The precise mechanisms of mTORC1 lysosomal transport remain unclear.
Purpose of the Study:
- To elucidate the mechanism of mTORC1 dissociation from lysosomes.
- To investigate the role of microtubules and motor proteins in mTORC1 regulation.
- To understand how amino acid availability controls mTORC1 activity.
Main Methods:
- Investigated mTORC1 localization and activity under conditions of amino acid scarcity.
- Utilized microtubule disruption and KIF11 knockdown experiments.
- Performed mechanistic studies to identify protein interactions.
Main Results:
- Microtubules and KIF11 are essential for mTORC1 dissociation from lysosomes during amino acid starvation.
- Disruption of microtubules or KIF11 knockdown leads to sustained lysosomal localization of mTORC1.
- mTORC1 interacts with the motor domain of KIF11, facilitating its movement along microtubules.
Conclusions:
- Identified a novel regulatory mechanism for mTORC1 based on amino acid availability.
- Demonstrated a new role for KIF11 and microtubules in controlling mTOR signaling.
- mTORC1 movement from lysosomes is mediated by KIF11-dependent transport along microtubules.
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