Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental signals for cell growth and metabolism.
• mTORC1 activation occurs at the lysosome via interaction with GTP-bound Rheb GTPase.
• The regulation of Rheb GTPase activity remains poorly understood.

Purpose of the Study:

• To elucidate the regulatory mechanism governing Rheb GTPase activity.
• To investigate the role of post-translational modifications in Rheb regulation.
• To understand how Rheb activity impacts mTORC1 signaling and tumor growth.

Main Methods:

• Investigated the role of ubiquitination in regulating Rheb nucleotide-bound status.
• Identified RNF152 as a lysosome-anchored E3 ligase catalyzing Rheb ubiquitination.
• Examined the effect of epidermal growth factor (EGF) on Rheb deubiquitination via AKT-dependent USP4 phosphorylation.

Main Results:

• Ubiquitination dynamically controls the nucleotide-bound status of Rheb GTPase.
• RNF152-mediated ubiquitination promotes Rheb binding to the TSC complex.
• EGF signaling, via AKT and USP4, deubiquitinates Rheb, releasing it from the TSC complex.
• Rheb ubiquitination is functionally linked to mTORC1 signaling and tumor growth.

Conclusions:

• Rheb ubiquitination and deubiquitination, catalyzed by RNF152 and USP4 respectively, dynamically regulate Rheb-mediated mTORC1 activation.
• This ubiquitination-deubiquitination axis provides a novel regulatory mechanism for mTORC1 signaling.
• The findings offer insights into mTORC1 pathway dysregulation in tumor development.