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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.<\/jats:p>","DOI":"10.1073\/pnas.0903621106","type":"journal-article","created":{"date-parts":[[2009,5,20]],"date-time":"2009-05-20T21:51:09Z","timestamp":1242856269000},"page":"8923-8928","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":86,"title":["Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy"],"prefix":"10.1073","volume":"106","author":[{"given":"Xiaoming","family":"Zhou","sequence":"first","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuneo","family":"Ikenoue","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Chen","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, and"},{"name":"Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093-0815"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Inoki","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Liang","family":"Guan","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Biological Chemistry, and"},{"name":"Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109; 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