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NOP53 Suppresses Autophagy through ZKSCAN3-Dependent and -Independent Pathways
Young-Eun Cho1, Yong-Jun Kim1, Sun Lee1
1Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02453, Korea.
Abstract:
Autophagy is an evolutionally conserved process that recycles aged or damaged intracellular components through a lysosome-dependent pathway. Although this multistep process is propagated in the cytoplasm by the orchestrated activity of the mTOR complex, phosphatidylinositol 3-kinase, and a set of autophagy-related proteins (ATGs), recent investigations have suggested that autophagy is tightly regulated by nuclear events. Thus, it is conceivable that the nucleolus, as a stress-sensing and -responding intranuclear organelle, plays a role in autophagy regulation, but much is unknown concerning the nucleolar controls in autophagy. In this report, we show a novel nucleolar-cytoplasmic axis that regulates the cytoplasmic autophagy process: nucleolar protein NOP53 regulates the autophagic flux through two divergent pathways, the ZKSCAN3-dependent and -independent pathways. In the ZKSCAN3-dependent pathway, NOP53 transcriptionally activates a master autophagy suppressor ZKSCAN3, thereby inhibiting MAP1LC3B/LC3B induction and autophagy propagation. In the ZKSCAN3-independent pathway, NOP53 physically interacts with histone H3 to dephosphorylate S10 of H3, which, in turn, transcriptionally downregulates the ATG7 and ATG12 expressions. Our results identify nucleolar protein NOP53 as an upstream regulator of the autophagy process.
Insights
Nucleolar protein NOP53 regulates autophagy through two pathways: it activates the autophagy suppressor ZKSCAN3 and dephosphorylates histone H3, inhibiting key autophagy genes. This reveals a novel nucleolar control over cellular recycling.
Area of Science:
- Cell Biology
- Molecular Biology
- Autophagy Research
Background:
- Autophagy is a conserved cellular recycling process crucial for maintaining homeostasis.
- While primarily cytoplasmic, autophagy is increasingly recognized as being regulated by nuclear events.
- The nucleolus's role in autophagy regulation remains largely unexplored.
Purpose of the Study:
- To investigate the nucleolus's role in regulating cytoplasmic autophagy.
- To identify novel nucleolar factors controlling autophagic flux.
- To elucidate the molecular mechanisms linking nucleolar function to autophagy.
Main Methods:
- Investigated the function of nucleolar protein NOP53 in autophagy.
- Utilized molecular biology techniques to study NOP53's interactions and regulatory pathways.
- Analyzed the impact of NOP53 on autophagy-related gene expression (ZKSCAN3, ATG7, ATG12) and protein levels (LC3B).
Main Results:
- Identified a novel nucleolar-cytoplasmic axis regulating autophagy.
- NOP53 was found to regulate autophagic flux via both ZKSCAN3-dependent and -independent pathways.
- NOP53 transcriptionally activates ZKSCAN3, inhibiting autophagy, and interacts with histone H3 to downregulate ATG7 and ATG12 expression.
Conclusions:
- Nucleolar protein NOP53 acts as an upstream regulator of the autophagy process.
- NOP53 controls autophagic flux through distinct molecular mechanisms involving transcriptional regulation and histone modification.
- This study uncovers a significant link between nucleolar function and cytoplasmic autophagy.
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