Identification of Annexin A2 as a key mTOR target to induce roller coaster pattern of autophagy fluctuation in stress
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Updated: Dec 11, 2025
Study of Protein-protein Interactions in Autophagy Research
Published on: September 9, 2017
Subhadip Mukhopadhyay1, Prakash P Praharaj1, Prajna P Naik1
1Department of Life Science, National Institute of Technology Rourkela, Rourkela-769008, India.
Abstract:
Autophagy can either be cytoprotective or promote cell death in a context-dependent manner in response to stress. How autophagy leads to autophagy dependent cell death requires further clarification. In this study, we document a nonlinear roller coaster form of autophagy oscillation when cells are subjected to different stress conditions. Serum starvation induces an initial primary autophagic peak at 6 h, that helps to replenish cells with de novo fluxed nutrients, but protracted stress lead to a secondary autophagic peak around 48 h. Time kinetic studies indicate that the primary autophagic peak is reversible, whereas the secondary autophagic peak is irreversible and leads to cell death. Key players involved in different stages of autophagy including initiation, elongation and degradation during this oscillatory sequence were identified. A similar molecular pattern was intensified under apoptosis-deficient conditions. mTOR was the central molecule regulating this autophagic activity, and upon knockdown a steady increase of autophagy without any non-linear fluctuation was evident. An unbiased proteome screening approach was employed to identify the autophagy molecules potentially regulating these autophagic peaks. Our proteomics analysis has identified Annexin A2 as a stress-induced protein to implicate in autophagy fluctuation and its deficiency reduced autophagy. Moreover, we report that mTOR in its phosphorylated condition interacts with Annexin A2 to induce autophagy fluctuation by altering its cellular localization. The work highlights the molecular mechanism of a mTOR-dependent roller coaster fluctuation of autophagy and autophagy dependent cell death during prolong stress.
Insights
Autophagy exhibits a nonlinear oscillation during prolonged stress, with a reversible early peak and an irreversible late peak causing cell death. This roller coaster pattern is regulated by mTOR and Annexin A2.
Area of Science:
- Cellular Biology
- Molecular Biology
- Stress Response
Background:
- Autophagy's dual role in cell survival and death is context-dependent.
- The precise mechanisms driving autophagy-dependent cell death remain unclear.
- Understanding autophagy regulation under stress is crucial for therapeutic interventions.
Purpose of the Study:
- To elucidate the dynamic regulation of autophagy during prolonged cellular stress.
- To identify key molecular players involved in autophagy oscillations and cell death.
- To investigate the role of mTOR and Annexin A2 in stress-induced autophagy.
Main Methods:
- Induction of cellular stress (serum starvation) and monitoring of autophagy dynamics over time.
- Kinetic studies to differentiate reversible and irreversible autophagic phases.
- Genetic manipulation (mTOR knockdown) to assess its regulatory role.
- Proteomics screening to identify novel autophagy-associated proteins.
- Investigation of protein-protein interactions (mTOR and Annexin A2) and cellular localization.
Main Results:
- Observed a nonlinear, roller coaster-like oscillation in autophagy activity under stress.
- Identified a reversible primary autophagic peak (6h) and an irreversible secondary peak (48h) leading to cell death.
- mTOR acts as a central regulator; its knockdown abolishes oscillations, leading to steady autophagy.
- Proteomics identified Annexin A2 as a stress-induced protein crucial for autophagy fluctuation.
- Phosphorylated mTOR interacts with Annexin A2, influencing its localization and autophagy.
Conclusions:
- Prolonged stress induces a distinct, oscillatory pattern of autophagy, termed a 'roller coaster' effect.
- The secondary, irreversible autophagic peak is a critical driver of autophagy-dependent cell death.
- The mTOR-Annexin A2 interaction is a key molecular mechanism underlying stress-induced autophagy oscillation and subsequent cell death.
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