Rapid proteasomal degradation of the stress response protein REDD2 is mediated by the E3 ligase HUWE1

Area of Science:

• Cellular biology
• Molecular mechanisms
• Protein regulation

Background:

• Stress response proteins regulated in development and DNA damage (REDD)1 and REDD2 inhibit mechanistic target of rapamycin complex 1 (mTORC1).
• REDD1 degradation occurs via chaperone-mediated autophagy (CMA) and the ubiquitin proteasome system (UPS).
• Mechanisms controlling REDD2 cellular abundance remain largely uncharacterized.

Purpose of the Study:

• To investigate the molecular mechanisms governing REDD2 cellular abundance.
• To compare the degradation pathways of REDD1 and REDD2.

Main Methods:

• Genetic and pharmacologic interventions were employed to modulate protein synthesis and degradation.
• Protein half-lives were assessed.
• The role of CMA and UPS in REDD2 degradation was examined.

Main Results:

• Both REDD1 and REDD2 exhibit rapid degradation with half-lives under 20 minutes.
• REDD2 expression decelerated REDD1 degradation, indicating overlapping degradation pathways.
• Unlike REDD1, REDD2 degradation was not enhanced by CMA activation.
• REDD2 degradation is mediated by the UPS, specifically involving the E3 ligase HUWE1 and lysine residues K119/K120.

Conclusions:

• Cellular abundance of both REDD1 and REDD2 is primarily controlled by protein stability.
• REDD2 degradation is distinct from REDD1, relying on the UPS rather than CMA.
• HUWE1 and specific lysine residues are crucial for REDD2 proteasomal degradation.