| RRC ID |
78037
|
| 著者 |
Lee D, Yoon E, Ham SJ, Lee K, Jang H, Woo D, Lee DH, Kim S, Choi S, Chung J.
|
| タイトル |
Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
15(1)
|
| ページ |
468
|
| 公開日 |
2024-1-11
|
| DOI |
10.1038/s41467-024-44747-9
|
| PII |
10.1038/s41467-024-44747-9
|
| PMID |
38212312
|
| PMC |
PMC10784524
|
| MeSH |
Animals
Diabetes Mellitus, Type 2* / genetics
Drosophila
Insulin Resistance* / genetics
Neurons
Ubiquitin Thiolesterase / genetics
|
| IF |
12.121
|
| リソース情報 |
| ショウジョウバエ |
7037R-1
1877R-1
7788R-1
HMS01553
3938R-2
5072R-3
GL00039
HMS00476
4006R-1
DGRC#108125
DGRC#108184 |
