mTOR-sensitive translation: Cleared fog reveals more trees

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Protein translation is crucial for cellular responses, with the mechanistic target of rapamycin (mTOR) pathway being a key regulator.
• mTOR influences global protein synthesis, but specific messenger RNAs (mRNAs) exhibit heightened sensitivity to its activity.
• Previous studies cataloging mTOR-sensitive mRNAs yielded conflicting results between ribosome-profiling and polysome-profiling techniques.

Purpose of the Study:

• To reconcile discrepancies in identifying mTOR-sensitive mRNAs observed between different profiling methods.
• To characterize the features and functions of mTOR-sensitive non-5'-terminal oligopyrimidine (non-TOP) mRNAs.
• To advance the understanding of how mTOR regulates translation for specific mRNA subsets.

Main Methods:

• Comparative analysis of ribosome-profiling and polysome-profiling data to identify mTOR-sensitive mRNAs.
• Genome-wide characterization of the 5' untranslated regions (5'UTRs) of identified mTOR-sensitive mRNAs.
• Assessment of translation initiation factor requirements and biological functions for distinct mRNA groups.

Main Results:

• Analytical and technical biases in ribosome-profiling were identified as a cause for under-detection of certain mTOR-sensitive mRNAs.
• Polysome-profiling data indicated that mTOR regulates both 5'-terminal oligopyrimidine (TOP) and non-TOP mRNAs.
• Non-TOP mTOR-sensitive mRNAs were further classified into two subsets with differing translation initiation factor dependencies and biological roles.

Conclusions:

• The study resolves inconsistencies in identifying mTOR-sensitive mRNAs by highlighting methodological limitations.
• It reveals that mTOR regulates a broader set of mRNAs than previously thought, including distinct non-TOP mRNA populations.
• These findings refine our comprehension of mTOR's role in translational control and cellular signaling.