IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39151-8.html
   My bibliography  Save this article

Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid

Author

Listed:
  • Severin Lechner

    (Technical University of Munich)

  • Raphael R. Steimbach

    (Cancer Drug Development, German Cancer Research Center (DKFZ)
    Biosciences Faculty, Heidelberg University)

  • Longlong Wang

    (Friedrich Miescher Institute for Biomedical Research
    Faculty of Sciences, University of Basel)

  • Marshall L. Deline

    (Technical University of Munich)

  • Yun-Chien Chang

    (Technical University of Munich)

  • Tobias Fromme

    (Technical University of Munich
    Technical University of Munich)

  • Martin Klingenspor

    (Technical University of Munich
    Technical University of Munich
    Technical University of Munich)

  • Patrick Matthias

    (Friedrich Miescher Institute for Biomedical Research
    Faculty of Sciences, University of Basel)

  • Aubry K. Miller

    (Cancer Drug Development, German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Guillaume Médard

    (Technical University of Munich)

  • Bernhard Kuster

    (Technical University of Munich
    German Cancer Consortium (DKTK)
    Technical University of Munich)

Abstract

Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.

Suggested Citation

  • Severin Lechner & Raphael R. Steimbach & Longlong Wang & Marshall L. Deline & Yun-Chien Chang & Tobias Fromme & Martin Klingenspor & Patrick Matthias & Aubry K. Miller & Guillaume Médard & Bernhard Ku, 2023. "Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39151-8
    DOI: 10.1038/s41467-023-39151-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39151-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-39151-8?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. Todd J. Cohen & Andrew W. Hwang & Clark R. Restrepo & Chao-Xing Yuan & John Q. Trojanowski & Virginia M. Y. Lee, 2015. "An acetylation switch controls TDP-43 function and aggregation propensity," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    2. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Wenting Guo & Maximilian Naujock & Laura Fumagalli & Tijs Vandoorne & Pieter Baatsen & Ruben Boon & Laura Ordovás & Abdulsamie Patel & Marc Welters & Thomas Vanwelden & Natasja Geens & Tine Tricot & V, 2017. "HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    4. Yang Hai & Stephen A. Shinsky & Nicholas J. Porter & David W. Christianson, 2017. "Histone deacetylase 10 structure and molecular function as a polyamine deacetylase," Nature Communications, Nature, vol. 8(1), pages 1-9, August.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Guilherme Reis-de-Oliveira & Victor Corasolla Carregari & Gabriel Rodrigues dos Reis de Sousa & Daniel Martins-de-Souza, 2024. "OmicScope unravels systems-level insights from quantitative proteomics data," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

    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. Manohar Kodavati & Haibo Wang & Wenting Guo & Joy Mitra & Pavana M. Hegde & Vincent Provasek & Vikas H. Maloji Rao & Indira Vedula & Aijun Zhang & Sankar Mitra & Alan E. Tomkinson & Dale J. Hamilton &, 2024. "FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Rebecca San Gil & Dana Pascovici & Juliana Venturato & Heledd Brown-Wright & Prachi Mehta & Lidia Madrid San Martin & Jemma Wu & Wei Luan & Yi Kit Chui & Adekunle T. Bademosi & Shilpa Swaminathan & Se, 2024. "A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    3. Alexis Osseni & Aymeric Ravel-Chapuis & Edwige Belotti & Isabella Scionti & Yann-Gaël Gangloff & Vincent Moncollin & Laetitia Mazelin & Remi Mounier & Pascal Leblanc & Bernard J. Jasmin & Laurent Scha, 2022. "Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Jorge Garcia Morato & Friederike Hans & Felix Zweydorf & Regina Feederle & Simon J. Elsässer & Angelos A. Skodras & Christian Johannes Gloeckner & Emanuele Buratti & Manuela Neumann & Philipp J. Kahle, 2022. "Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Saumyak Mukherjee & Lars V. Schäfer, 2023. "Thermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Leonie G. Graf & Carlos Moreno-Yruela & Chuan Qin & Sabrina Schulze & Gottfried J. Palm & Ole Schmöker & Nancy Wang & Dianna M. Hocking & Leila Jebeli & Britta Girbardt & Leona Berndt & Babett Dörre &, 2024. "Distribution and diversity of classical deacylases in bacteria," Nature Communications, Nature, vol. 15(1), pages 1-31, 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:14:y:2023:i:1:d:10.1038_s41467-023-39151-8. 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.