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Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways

Title
Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways
Authors
Cho, Jin HwaKim, KidaeKim, Sung AhPark, SungryulPark, Bi-OhKim, Jong-HwanKim, Seon-YoungKwon, Min JeeHan, Myeong HoonLee, Sung BaePark, Byoung ChulPark, Sung GooKim, Jeong-HoonKim, Sunhong
DGIST Authors
Lee, Sung Bae
Issue Date
2021-03
Citation
Cell Death and Differentiation, 28(3), 900-914
Type
Article
Article Type
Article
Keywords
E3 UBIQUITIN LIGASEBETA-TRCPDEGRADATIONPHOSPHORYLATIONDUBACELLMETABOLISMACTIVATIONEXPRESSIONINHIBITOR
ISSN
1350-9047
Abstract
The mammalian Target of Rapamycin (mTOR) pathway regulates a variety of physiological processes, including cell growth and cancer progression. The regulatory mechanisms of these signals are extremely complex and comprise many feedback loops. Here, we identified the deubiquitinating enzyme ovarian tumor domain-containing protein 5 (OTUD5) as a novel positive regulator of the mTOR complex (mTORC) 1 and 2 signaling pathways. We demonstrated that OTUD5 stabilized β-transducin repeat-containing protein 1 (βTrCP1) proteins via its deubiquitinase (DUB) activity, leading to the degradation of Disheveled, Egl-10, and pleckstrin domain-containing mTOR-interacting protein (DEPTOR), which is an inhibitory protein of mTORC1 and 2. We also showed that mTOR directly phosphorylated OTUD5 and activated its DUB activity. RNA sequencing analysis revealed that OTUD5 regulates the downstream gene expression of mTOR. Additionally, OTUD5 depletion elicited several mTOR-related phenotypes such as decreased cell size and increased autophagy in mammalian cells as well as the suppression of a dRheb-induced curled wing phenotype by RNA interference of Duba, a fly ortholog of OTUD5, in Drosophila melanogaster. Furthermore, OTUD5 knockdown inhibited the proliferation of the cancer cell lines with mutations activating mTOR pathway. Our results suggested a positive feedback loop between OTUD5 and mTOR signaling pathway. © 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
URI
http://hdl.handle.net/20.500.11750/12939
DOI
10.1038/s41418-020-00649-z
Publisher
Nature Publishing Group
Related Researcher
  • Author Lee, Sung Bae Laboratory of Neurodegenerative Diseases and Aging
  • Research Interests Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
Files:
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Collection:
Department of Brain SciencesLaboratory of Neurodegenerative Diseases and Aging1. Journal Articles


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