Cap-independent translation ensures mTOR expression and function upon protein synthesis inhibition

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• The mechanistic/mammalian target of rapamycin (mTOR) pathway regulates protein synthesis in response to nutrient and energy levels.
• While mTOR signaling is well-studied, the regulation of mTOR gene expression remains largely unknown.

Purpose of the Study:

• To investigate the mechanisms regulating human mTOR gene expression.
• To explore the role of the 5' untranslated region (UTR) in mTOR translation.
• To understand mTOR's function in cell-cycle progression under varying conditions.

Main Methods:

• Analysis of human mTOR transcript translation.
• RNA structure probing of the 5' UTR.
• Ribosomal subunit binding assays.
• Cell-cycle progression analysis under normal and hypoxic conditions.

Main Results:

• The human mTOR transcript undergoes cap-independent translation.
• The 5' UTR of mTOR acts as an RNA scaffold, directly binding the 40S ribosomal subunit.
• mTOR bypasses the cap requirement for translation in both normal and hypoxic states.
• Cap-independent mTOR translation is essential for inducing cell-cycle progression into S phase.

Conclusions:

• A novel regulatory mechanism for mTOR gene expression is proposed, involving cap-independent translation.
• This mechanism integrates global protein synthesis regulation with mTOR activity, particularly under stress.
• The findings highlight the importance of translational control in cellular processes like cell-cycle progression.