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

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Title
Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways
Author(s)
Jin Hwa Cho; Kidae Kim; Sung Ah Kim; Seongryul Park; Bi-Oh Park; Jong Hwan KimSeon-Young Kim; M J Kwon; M H Han; S B Lee; Byoung Chul ParkSung Goo ParkJeong Hoon Kim; Sunhong Kim
Bibliographic Citation
Cell Death and Differentiation, vol. 28, no. 3, pp. 900-914
Publication Year
2021
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.
ISSN
1350-9047
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41418-020-00649-z
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
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