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Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy.

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.

SUBMITTER: Zhou X

PROVIDER: S-EPMC2690031 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy.

Zhou Xiaoming X Ikenoue Tsuneo T Chen Xiaowei X Li Li L Inoki Ken K Guan Kun-Liang KL

Proceedings of the National Academy of Sciences of the United States of America 20090520 22

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 constitutiv ...[more]

PMID: 19458266

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Project description:AimsElectronic cigarettes (e-cigarettes) are proposed to be a safer alternative to tobacco cigarettes. Hence, we evaluated if e-cigarette vapors (eCV) impair cellular proteostasis similar to cigarette smoke exposure.ResultsFirst, we evaluated the impact of eCV exposure (2.5 or 7.5 mg) on Beas2b cells that showed significant increase in accumulation of total polyubiquitinated proteins (Ub, insoluble fractions) with time-dependent decrease in proteasomal activities from 1 h (p < 0.05), 3 h (p < 0.001) to 6 h (p < 0.001) of eCV exposure compared to room air control. We verified that even minimal eCV exposure (1 h) induces valosin-containing protein (VCP; p < 0.001), sequestosome-1/p62 (aberrant autophagy marker; p < 0.05), and aggresome formation (total poly-Ub-accumulation; p < 0.001) using immunoblotting (IB), fluorescence microscopy, and immunoprecipitation (IP). The inhibition of protein synthesis by 6 h of cycloheximide (50 μg/ml) treatment significantly (p < 0.01) alleviates eCV-induced (1 h) aggresome bodies. We also observed that eCV (1 h)-induced protein aggregation can activate oxidative stress, apoptosis (caspase-3/7), and senescence (p < 0.01) compared to room air controls. We verified using an autophagy inducer carbamazepine (20 μM, 6 h) or cysteamine (250 μM; 6 h, antioxidant) that eCV-induced changes in oxidative stress, poly-ub-accumulation, proteasomal activity, autophagy, apoptosis, and/or senescence could be controlled by autophagy induction. We further confirmed the role of acute eCV exposure on autophagy impairment in murine lungs (C57BL/6 and CD1) by IB (Ub, p62, VCP) and IP (VCP, p62), similar to in-vitro experiments.InnovationIn this study, we report for the first time that eCV exposure induces proteostasis/autophagy impairment leading to oxidative stress, apoptosis, and senescence that can be ameliorated by an autophagy inducer.ConclusioneCV-induced autophagy impairment and aggresome formation suggest their potential role in chronic obstructive pulmonary disease-emphysema pathogenesis. Antioxid. Redox Signal. 00, 000-000.

Dataset Information

Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy.

Publications

Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy.

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