Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
SCIE
SCOPUS
- Title
- Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
- Authors
- Lee, Daewon; Yoon, Eunju; Ham, Su Jin; Lee, Kunwoo; Jang, Hansaem; Woo, Daihn; Lee, Da Hyun; Kim, Sehyeon; Choi, Sekyu; Chung, Jongkyeong
- Date Issued
- 2024-01
- Publisher
- Nature Publishing Group
- Abstract
- AbstractDiabetic 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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/119979
- DOI
- 10.1038/s41467-024-44747-9
- Article Type
- Article
- Citation
- Nature Communications, vol. 15, no. 1, 2024-01
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