Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44747-9 |
| _version_ | 1797355671641915392 |
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| author | Daewon Lee Eunju Yoon Su Jin Ham Kunwoo Lee Hansaem Jang Daihn Woo Da Hyun Lee Sehyeon Kim Sekyu Choi Jongkyeong Chung |
| author_facet | Daewon Lee Eunju Yoon Su Jin Ham Kunwoo Lee Hansaem Jang Daihn Woo Da Hyun Lee Sehyeon Kim Sekyu Choi Jongkyeong Chung |
| author_sort | Daewon Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:15:25Z |
| format | Article |
| id | doaj.art-b2dcd46a31814745b014f9c6459a7b50 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T14:15:25Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b2dcd46a31814745b014f9c6459a7b502024-01-14T12:28:26ZengNature PortfolioNature Communications2041-17232024-01-0115112210.1038/s41467-024-44747-9Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in DrosophilaDaewon Lee0Eunju Yoon1Su Jin Ham2Kunwoo Lee3Hansaem Jang4Daihn Woo5Da Hyun Lee6Sehyeon Kim7Sekyu Choi8Jongkyeong Chung9Institute of Molecular Biology and Genetics, Seoul National UniversityInstitute of Molecular Biology and Genetics, Seoul National UniversityInstitute of Molecular Biology and Genetics, Seoul National UniversitySchool of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and TechnologyDepartment of Life Sciences, Pohang University of Science and TechnologyInstitute of Molecular Biology and Genetics, Seoul National UniversityInstitute of Molecular Biology and Genetics, Seoul National UniversityInstitute of Molecular Biology and Genetics, Seoul National UniversitySchool of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and TechnologyInstitute of Molecular Biology and Genetics, Seoul National UniversityAbstract 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.https://doi.org/10.1038/s41467-024-44747-9 |
| spellingShingle | Daewon Lee Eunju Yoon Su Jin Ham Kunwoo Lee Hansaem Jang Daihn Woo Da Hyun Lee Sehyeon Kim Sekyu Choi Jongkyeong Chung Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila Nature Communications |
| title | Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila |
| title_full | Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila |
| title_fullStr | Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila |
| title_full_unstemmed | Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila |
| title_short | Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila |
| title_sort | diabetic sensory neuropathy and insulin resistance are induced by loss of uchl1 in drosophila |
| url | https://doi.org/10.1038/s41467-024-44747-9 |
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