한빛사논문
Daewon Lee 1,2,5, Eunju Yoon 1,2,5, Su Jin Ham 1,2,5, Kunwoo Lee 3, Hansaem Jang 4, Daihn Woo 1, Da Hyun Lee 1,2, Sehyeon Kim 1,2, Sekyu Choi 3,4,* & Jongkyeong Chung 1,2,*
1Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea.
2School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
3School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
4Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
5These authors contributed equally: Daewon Lee, Eunju Yoon, Su Jin Ham.
*Corresponding authors: correspondence to Sekyu Choi or Jongkyeong Chung
Abstract
Diabetic sensory neuropathy (DSN) is one of the most common complications of type 2 diabetes (T2D), however the molecular mechanistic association between T2D and DSN remains elusive. Here we identify ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinase highly expressed in neurons, as a key molecule underlying T2D and DSN. Genetic ablation of UCHL1 leads to neuronal insulin resistance and T2D-related symptoms in Drosophila. Furthermore, loss of UCHL1 induces DSN-like phenotypes, including numbness to external noxious stimuli and axonal degeneration of sensory neurons in flies’ legs. Conversely, UCHL1 overexpression improves DSN-like defects of T2D model flies. UCHL1 governs insulin signaling by deubiquitinating insulin receptor substrate 1 (IRS1) and antagonizes an E3 ligase of IRS1, Cullin 1 (CUL1). Consistent with these results, genetic and pharmacological suppression of CUL1 activity rescues T2D- and DSN-associated phenotypes. Therefore, our findings suggest a complete set of genetic factors explaining T2D and DSN, together with potential remedies for the diseases.
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