Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy.
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.
Zhou
Xiaoming
X
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Ikenoue
Tsuneo
T
Chen
Xiaowei
X
Li
Li
L
Inoki
Ken
K
Guan
Kun-Liang
KL
D000818:Animals; D001343:Autophagy / Q000235:genetics; D004398:Dyneins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D017510:Protein Folding; D000076205:Ras Homolog Enriched in Brain Protein; D014157:Transcription Factors / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C519509:Crtc1 protein, mouse; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors; D004398:Dyneins; D020559:Monomeric GTP-Binding Proteins