HR3/RORα-mediated cholesterol sensing regulates TOR signaling

Area of Science:

• Cellular biology
• Molecular mechanisms
• Metabolic regulation

Background:

• Cholesterol is vital for cell function and organismal growth.
• Cellular mechanisms for sensing cholesterol and linking it to growth remain unclear.
• The mechanistic target of rapamycin (TOR) pathway is a master regulator of cell growth.

Purpose of the Study:

• To investigate how cells sense cholesterol levels and translate this into growth signals.
• To identify molecular players involved in cholesterol-mediated growth regulation.
• To explore the conserved nature of this signaling pathway across species.

Main Methods:

• Utilized Drosophila melanogaster as a model organism.
• Investigated the role of nuclear receptor HR3 in response to cholesterol.
• Examined the activation of the TOR pathway.
• Assessed non-genomic and genomic regulatory mechanisms.
• Validated findings in human cell lines.

Main Results:

• Cholesterol rapidly activates the TOR pathway in Drosophila tissues.
• Nuclear receptor HR3 is essential for cholesterol-induced TOR activation.
• HR3 directly binds cholesterol and activates TOR via a non-genomic mechanism upstream of Rag GTPases.
• HR3 also mediates longer-term responses through genomic regulation.
• RORα is required for cholesterol-mediated TOR activation in human cells.

Conclusions:

• HR3/RORα acts as a conserved sensor coupling cholesterol availability to TOR pathway activity.
• This signaling pathway provides a mechanism for cells to adjust growth based on cholesterol levels.
• Findings have implications for understanding cholesterol-related diseases and cancer.