Sirtuin 2 inhibits global protein synthesis via Rheb-GTPase degradation

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Biology

Background:

• Increased global protein synthesis is linked to aging-related diseases.
• Calorie restriction and protein synthesis inhibition show health benefits.
• Molecular regulators of protein synthesis are not fully understood.

Purpose of the Study:

• To investigate the role of SIRT2 in regulating global protein synthesis.
• To elucidate the molecular mechanism by which SIRT2 affects protein synthesis.
• To explore SIRT2 as a therapeutic target for diseases involving aberrant protein synthesis.

Main Methods:

• In vitro assays to assess protein synthesis.
• SIRT2 deficiency and overexpression models (cell culture and mice).
• Western blotting and ubiquitination assays to study Rheb degradation.
• Analysis of cardiac hypertrophy in mouse models.

Main Results:

• SIRT2 deficiency increases global protein synthesis; SIRT2 overexpression suppresses it.
• SIRT2 inhibits the mTORC1 pathway by deacetylating and promoting Rheb degradation.
• SIRT2-deficient mice show increased cardiac protein synthesis and hypertrophy.
• Rheb depletion rescues increased protein synthesis in SIRT2-inhibited cells.

Conclusions:

• SIRT2 negatively regulates global protein synthesis via the mTORC1/Rheb pathway.
• SIRT2-mediated Rheb degradation is crucial for controlling protein synthesis.
• SIRT2 activation presents a potential therapeutic avenue for diseases characterized by elevated protein synthesis.