Editors' ChoiceCell Biology

Rheb Permits Aggresome Formation

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Science Signaling  09 Jun 2009:
Vol. 2, Issue 74, pp. ec193
DOI: 10.1126/scisignal.274ec193

Cells have three mechanisms for handling misfolded proteins: (i) ubiquitin-mediated proteasomal degradation; (ii) autophagic targeting to lysosomes; and (iii) formation of insoluble perinuclear aggresomes. In addition, the mammalian target of rapamycin complex 1 (mTORC1) plays a key role in protein metabolism by stimulating translation and inhibiting autophagy. Rheb is the guanosine triphosphatase that activates mTORC1. Zhou et al. found that cells in which mTORC1 is constitutively active—through knockout of the components of its negative regulator, the tuberous sclerosis complex (TSC1 or TSC2)—exhibited less autophagy when the proteasome was inhibited than did cells in which mTORC1 activity was properly regulated. Surprisingly, the TSC-deficient cells exhibited decreased accumulation of polyubiquitinated proteins and defective aggresome formation, in contrast to cells in which autophagy was defective through mechanisms independent of mTORC1 activation. Inhibition of mTORC1 activity with rapamycin failed to restore aggresome formation, suggesting that Rheb may have an mTORC1-independent role in handling misfolded proteins. Constitutively active mutant Rheb inhibited aggresome formation when the proteasome was inhibited and prevented aggresome formation of the cystic fibrosis transmembrane conductance regulator mutant, which is ubiquitinated and aggregation prone, but failed to alter aggresome formation of a green fluorescent protein, which aggregates without ubiquitination. A dominant-negative mutant of Rheb inhibited aggresome formation and colocalized with aggresomes. The misfolded and ubiquitinated proteins are delivered to the perinuclear aggresome by microtubules. TSC-deficient cells exhibited less coimmunoprecipitation of ubiquitinated proteins with the minus end–directed microtubule motor dynein, suggesting that Rheb may regulate this process. Cells that cannot handle misfolded proteins tend to undergo apoptosis when exposed to proteasome inhibitors. TSC-deficient cells exhibited greater cell death in response to proteasomal inhibition, and this was not fully prevented by rapamycin but was reduced by knockdown of Rheb with silencing RNA. The activated Rheb mutant also sensitized cells to death induced by proteasome inhibition. Liver-specific knockout of TSC1 in mice prevented aggresome formation and triggered apoptosis in response to injection of a proteasome inhibitor. Thus, Rheb appears to have an mTORC1-independent role in delivery of misfolded proteins to aggresomes.

X. Zhou, T. Ikenoue, X. Chen, L. Li, K. Inoki, K.-L. Guan, Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proc. Natl. Acad. Sci. U.S.A. 106, 8923–8928 (2009). [Abstract] [Full Text]

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