IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-44747-9.html
   My bibliography  Save this article

Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila

Author

Listed:
  • Daewon Lee

    (Seoul National University
    Seoul National University)

  • Eunju Yoon

    (Seoul National University
    Seoul National University)

  • Su Jin Ham

    (Seoul National University
    Seoul National University)

  • Kunwoo Lee

    (Pohang University of Science and Technology)

  • Hansaem Jang

    (Pohang University of Science and Technology)

  • Daihn Woo

    (Seoul National University)

  • Da Hyun Lee

    (Seoul National University
    Seoul National University)

  • Sehyeon Kim

    (Seoul National University
    Seoul National University)

  • Sekyu Choi

    (Pohang University of Science and Technology
    Pohang University of Science and Technology)

  • Jongkyeong Chung

    (Seoul National University
    Seoul National University)

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.

Suggested Citation

  • Daewon Lee & Eunju Yoon & Su Jin Ham & Kunwoo Lee & Hansaem Jang & Daihn Woo & Da Hyun Lee & Sehyeon Kim & Sekyu Choi & Jongkyeong Chung, 2024. "Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44747-9
    DOI: 10.1038/s41467-024-44747-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-44747-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-44747-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Alexander Lachmann & Denis Torre & Alexandra B. Keenan & Kathleen M. Jagodnik & Hoyjin J. Lee & Lily Wang & Moshe C. Silverstein & Avi Ma’ayan, 2018. "Massive mining of publicly available RNA-seq data from human and mouse," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Ruisheng Song & Wei Peng & Yan Zhang & Fengxiang Lv & Hong-Kun Wu & Jiaojiao Guo & Yongxing Cao & Yanbin Pi & Xin Zhang & Li Jin & Mao Zhang & Peng Jiang & Fenghua Liu & Shaoshuai Meng & Xiuqin Zhang , 2013. "Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders," Nature, Nature, vol. 494(7437), pages 375-379, February.
    3. David S. Hewings & Johanna Heideker & Taylur P. Ma & Andrew P. AhYoung & Farid El Oualid & Alessia Amore & Gregory T. Costakes & Daniel Kirchhofer & Bradley Brasher & Thomas Pillow & Nataliya Popovych, 2018. "Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    4. Elisabeth Leroy & Rebecca Boyer & Georg Auburger & Barbara Leube & Gudrun Ulm & Eva Mezey & Gyongyi Harta & Michael J. Brownstein & Sobhanadditya Jonnalagada & Tanya Chernova & Anindya Dehejia & Chris, 1998. "The ubiquitin pathway in Parkinson's disease," Nature, Nature, vol. 395(6701), pages 451-452, October.
    5. Teresa A. Soucy & Peter G. Smith & Michael A. Milhollen & Allison J. Berger & James M. Gavin & Sharmila Adhikari & James E. Brownell & Kristine E. Burke & David P. Cardin & Stephen Critchley & Courtne, 2009. "An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer," Nature, Nature, vol. 458(7239), pages 732-736, April.
    6. Anil Kumar & Kumaran Sundaram & Jingyao Mu & Gerald W. Dryden & Mukesh K. Sriwastva & Chao Lei & Lifeng Zhang & Xiaolan Qiu & Fangyi Xu & Jun Yan & Xiang Zhang & Juw Won Park & Michael L. Merchant & H, 2021. "High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yuemin Ma & Lei Ding & Zhenhai Li & Chun Zhou, 2023. "Structural basis for TRIM72 oligomerization during membrane damage repair," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Gaopeng Hou & Wandy Beatty & Lili Ren & Yaw Shin Ooi & Juhee Son & Yinxing Zhu & Qingyu Sheng & Wanyi Huang & Dian Li & Constin Liu & Olivia L. Welsh & Danica M. Sutherland & Terence S. Dermody & Chen, 2025. "SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    3. Jonathan P. Ling & Alexei M. Bygrave & Clayton P. Santiago & Rogger P. Carmen-Orozco & Vickie T. Trinh & Minzhong Yu & Yini Li & Ying Liu & Kyra D. Bowden & Leighton H. Duncan & Jeong Han & Kamil Tane, 2022. "Cell-specific regulation of gene expression using splicing-dependent frameshifting," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Kenneth A. Wilson & Sudipta Bar & Eric B. Dammer & Enrique M. Carrera & Brian A. Hodge & Tyler A. U. Hilsabeck & Joanna Bons & George W. Brownridge & Jennifer N. Beck & Jacob Rose & Melia Granath-Pane, 2024. "OXR1 maintains the retromer to delay brain aging under dietary restriction," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Yongchang Zhu & Xiping Zhang & Meng Gao & Yanchao Huang & Yuanqing Tan & Avital Parnas & Sizhong Wu & Delin Zhan & Sheera Adar & Jinchuan Hu, 2024. "Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Nicholas Markarian & Kimberly M Van Auken & Dustin Ebert & Paul W Sternberg, 2024. "Enrichment on steps, not genes, improves inference of differentially expressed pathways," PLOS Computational Biology, Public Library of Science, vol. 20(3), pages 1-23, March.
    7. Hao Chen & Frederick J. King & Bin Zhou & Yu Wang & Carter J. Canedy & Joel Hayashi & Yang Zhong & Max W. Chang & Lars Pache & Julian L. Wong & Yong Jia & John Joslin & Tao Jiang & Christopher Benner , 2024. "Drug target prediction through deep learning functional representation of gene signatures," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. María Arroyo & Florian D. Hastert & Andreas Zhadan & Florian Schelter & Susanne Zimbelmann & Cathia Rausch & Anne K. Ludwig & Thomas Carell & M. Cristina Cardoso, 2022. "Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation," Nature Communications, Nature, vol. 13(1), pages 1-28, December.
    9. Debasish Paul & Stephen C. Kales & James A. Cornwell & Marwa M. Afifi & Ganesha Rai & Alexey Zakharov & Anton Simeonov & Steven D. Cappell, 2022. "Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Fei Xie & Bin Liu & Wen Qiao & Jing-zhen He & Jie Cheng & Zhao-yang Wang & Ya-min Hou & Xu Zhang & Bo-han Xu & Yun Zhang & Yu-guo Chen & Ming-xiang Zhang, 2024. "Smooth muscle NF90 deficiency ameliorates diabetic atherosclerotic calcification in male mice via FBXW7-AGER1-AGEs axis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. George S. Biggs & Emma E. Cawood & Aini Vuorinen & William J. McCarthy & Harry Wilders & Ioannis G. Riziotis & Antonie J. Zouwen & Jonathan Pettinger & Luke Nightingale & Peiling Chen & Andrew J. Powe, 2025. "Robust proteome profiling of cysteine-reactive fragments using label-free chemoproteomics," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    12. Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Gang Xue & Jianing Xie & Matthias Hinterndorfer & Marko Cigler & Lara Dötsch & Hana Imrichova & Philipp Lampe & Xiufen Cheng & Soheila Rezaei Adariani & Georg E. Winter & Herbert Waldmann, 2023. "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    15. Isabel Tundidor & Marta Seijo-Vila & Sandra Blasco-Benito & María Rubert-Hernández & Sandra Adámez & Clara Andradas & Sara Manzano & Isabel Álvarez-López & Cristina Sarasqueta & María Villa-Morales & , 2023. "Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Benjamin J Heil & Jake Crawford & Casey S Greene, 2023. "The effect of non-linear signal in classification problems using gene expression," PLOS Computational Biology, Public Library of Science, vol. 19(3), pages 1-12, March.
    17. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. repec:plo:pone00:0013175 is not listed on IDEAS
    19. Juliane Tschuck & Lea Theilacker & Ina Rothenaigner & Stefanie A. I. Weiß & Banu Akdogan & Van Thanh Lam & Constanze Müller & Roman Graf & Stefanie Brandner & Christian Pütz & Tamara Rieder & Philippe, 2023. "Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    20. Xiaotao Zhang & Huaming Li & Yichen Gu & An Ping & Jiarui Chen & Qia Zhang & Zhouhan Xu & Junjie Wang & Shenjie Tang & Rui Wang & Jianan Lu & Lingxiao Lu & Chenghao Jin & Ziyang Jin & Jianmin Zhang & , 2025. "Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    21. Naoko Iida & Ai Okada & Yoshihisa Kobayashi & Kenichi Chiba & Yasushi Yatabe & Yuichi Shiraishi, 2025. "Systematically developing a registry of splice-site creating variants utilizing massive publicly available transcriptome sequence data," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44747-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.