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PNAS 106 (22): 8923-8928

Copyright © 2009 by the National Academy of Sciences.


Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy

Xiaoming Zhoua, Tsuneo Ikenouea, Xiaowei Chena, Li Lib,c, Ken Inokia, and Kun-Liang Guana,b,c,d,1

aLife Sciences Institute, bDepartment of Biological Chemistry, and dInstitute of Gerontology, University of Michigan, Ann Arbor, MI 48109; and cDepartment of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093-0815

Communicated by Dennis A. Carson, University of California at San Diego, School of Medicine, La Jolla, CA, April 2, 2009

Received for publication March 16, 2009.

Abstract: Perinuclear aggresome formation is a key mechanism to dispose of misfolded proteins that exceed the degradative capacity of ubiquitin–proteasome and autophagy–lysosome systems. Functional blockade of either degradative system leads to an enhanced aggresome formation. The tuberous sclerosis complex–Ras homologue enriched in brain–mammalian target of rapamycin (TSC–Rheb–mTOR) pathway is known to play a central role in modulating protein synthesis and autophagy. However, in spite of the constitutive activation of mTOR and the abrogated autophagy activity in TSC1- or TSC2-deficient cells, the TSC mutant cells are defective in aggresome formation and undergo apoptosis upon misfolded protein accumulation both in vitro and in vivo. High Rheb activity in TSC mutant cells inhibits aggresome formation and sensitizes cell death in response to misfolded proteins. Surprisingly, this previously unrecognized function of Rheb is independent of TOR complex 1. Active Rheb disrupts the interaction between dynein and misfolded protein cargos, and therefore blocks aggresome formation by inhibiting dynein-dependent transportation of misfolded proteins. This study reveals a function of Rheb in controlling misfolded protein metabolism by modulating aggresome formation.

Key Words: mammalian target of rapamycin • tuberous sclerosis complex

Author contributions: X.Z. and K.-L.G. designed research; X.Z., T.I., X.C., L.L., and K.I. performed research; X.Z. and K.-L.G. analyzed data; and X.Z. and K.-L.G. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: kuguan{at}

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