한빛사논문
- 조회1,804
Jin Hwa Cho1, Kidae Kim1,2, Sung Ah Kim1,3, Sungryul Park1,3, Bi-Oh Park1,4, Jong-Hwan Kim5, Seon-Young Kim3,5, Min Jee Kwon6, Myeong Hoon Han6, Sung Bae Lee6, Byoung Chul Park1,2, Sung Goo Park1,3,*, Jeong-Hoon Kim1,3,*, Sunhong Kim1,7,8,*
1Disease Target Structure Research Center, KRIBB, Daejeon 34141, Republic of Korea
2Department of Proteome Structural Biology, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
3Department of Functional Genomics, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
4College of Pharmacy, Chungbuk National University, Cheongju 34113, Republic of Korea
5Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Republic of Korea
6Department of Brain & Cognitive Sciences, DGIST, Daegu 42988, Republic of Korea
7Department of Biomolecular Science, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
8Present address: Drug Discovery Center, Life Sciences, LG Chem, Seoul 07796, Republic of Korea
*Correspondence to Sung Goo Park or Jeong-Hoon Kim or Sunhong Kim.
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.
논문정보
- Research article
- 2020년 10월 (BRIC 등록일 2020-11-03)
- 국내 연구진
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