IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-25944-2.html
   My bibliography  Save this article

OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity

Author

Listed:
  • Esther Hoste

    (VIB Center for Inflammation Research
    Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Kim Lecomte

    (VIB Center for Inflammation Research
    Ghent University)

  • Karl Annusver

    (Karolinska Institutet)

  • Niels Vandamme

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Jana Roels

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Sophia Maschalidi

    (VIB Center for Inflammation Research
    Ghent University)

  • Lien Verboom

    (VIB Center for Inflammation Research
    Ghent University)

  • Hanna-Kaisa Vikkula

    (VIB Center for Inflammation Research
    Ghent University)

  • Mozes Sze

    (VIB Center for Inflammation Research
    Ghent University)

  • Lisette Van Hove

    (VIB Center for Inflammation Research
    Ghent University)

  • Kevin Verstaen

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Arne Martens

    (VIB Center for Inflammation Research
    Ghent University)

  • Tino Hochepied

    (VIB Center for Inflammation Research
    Ghent University)

  • Yvan Saeys

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Kodi Ravichandran

    (VIB Center for Inflammation Research
    Ghent University
    University of Virginia)

  • Maria Kasper

    (Karolinska Institutet)

  • Geert van Loo

    (VIB Center for Inflammation Research
    Ghent University
    Cancer Research Institute Ghent (CRIG))

Abstract

OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 or keratinocyte-specific deletion of Fadd and Mlkl completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.

Suggested Citation

  • Esther Hoste & Kim Lecomte & Karl Annusver & Niels Vandamme & Jana Roels & Sophia Maschalidi & Lien Verboom & Hanna-Kaisa Vikkula & Mozes Sze & Lisette Van Hove & Kevin Verstaen & Arne Martens & Tino , 2021. "OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25944-2
    DOI: 10.1038/s41467-021-25944-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-25944-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-021-25944-2?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. William J. Kaiser & Jason W. Upton & Alyssa B. Long & Devon Livingston-Rosanoff & Lisa P. Daley-Bauer & Razqallah Hakem & Tamara Caspary & Edward S. Mocarski, 2011. "RIP3 mediates the embryonic lethality of caspase-8-deficient mice," Nature, Nature, vol. 471(7338), pages 368-372, March.
    2. Andrew Oberst & Christopher P. Dillon & Ricardo Weinlich & Laura L. McCormick & Patrick Fitzgerald & Cristina Pop & Razq Hakem & Guy S. Salvesen & Douglas R. Green, 2011. "Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis," Nature, Nature, vol. 471(7338), pages 363-367, March.
    3. Lucia Taraborrelli & Nieves Peltzer & Antonella Montinaro & Sebastian Kupka & Eva Rieser & Torsten Hartwig & Aida Sarr & Maurice Darding & Peter Draber & Tobias L. Haas & Ayse Akarca & Teresa Marafiot, 2018. "LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    4. Nieves Peltzer & Maurice Darding & Antonella Montinaro & Peter Draber & Helena Draberova & Sebastian Kupka & Eva Rieser & Amanda Fisher & Ciaran Hutchinson & Lucia Taraborrelli & Torsten Hartwig & Elo, 2018. "LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis," Nature, Nature, vol. 557(7703), pages 112-117, May.
    5. Fumiyo Ikeda & Yonathan Lissanu Deribe & Sigrid S. Skånland & Benjamin Stieglitz & Caroline Grabbe & Mirita Franz-Wachtel & Sjoerd J. L. van Wijk & Panchali Goswami & Vanja Nagy & Janos Terzic & Fumin, 2011. "SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis," Nature, Nature, vol. 471(7340), pages 637-641, March.
    6. Elena Rivkin & Stephanie M. Almeida & Derek F. Ceccarelli & Yu-Chi Juang & Teresa A. MacLean & Tharan Srikumar & Hao Huang & Wade H. Dunham & Ryutaro Fukumura & Gang Xie & Yoichi Gondo & Brian Raught , 2013. "The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis," Nature, Nature, vol. 498(7454), pages 318-324, June.
    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. Hannah Schünke & Ulrike Göbel & Ivan Dikic & Manolis Pasparakis, 2021. "OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Chao-Yu Yang & Yi-Chun Tseng & Yi-Fan Tu & Bai-Jiun Kuo & Li-Chung Hsu & Chia-I Lien & You-Sheng Lin & Yin-Ting Wang & Yen-Chen Lu & Tsung-Wei Su & Yu-Chih Lo & Su-Chang Lin, 2024. "Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yi Luan & Wenying Long & Lisi Dai & Panfeng Tao & Zhifen Deng & Zongping Xia, 2024. "Linear ubiquitination regulates the KSHV replication and transcription activator protein to control infection," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Yesheng Fu & Lei Li & Xin Zhang & Zhikang Deng & Ying Wu & Wenzhe Chen & Yuchen Liu & Shan He & Jian Wang & Yuping Xie & Zhiwei Tu & Yadi Lyu & Yange Wei & Shujie Wang & Chun-Ping Cui & Cui Hua Liu & , 2024. "Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Chao-Yu Yang & Chia-I Lien & Yi-Chun Tseng & Yi-Fan Tu & Arkadiusz W. Kulczyk & Yen-Chen Lu & Yin-Ting Wang & Tsung-Wei Su & Li-Chung Hsu & Yu-Chih Lo & Su-Chang Lin, 2024. "Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Maria C. Tanzer & Isabell Bludau & Che A. Stafford & Veit Hornung & Matthias Mann, 2021. "Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Joo-Hui Han & Rajendra Karki & R. K. Subbarao Malireddi & Raghvendra Mall & Roman Sarkar & Bhesh Raj Sharma & Jonathon Klein & Harmut Berns & Harshan Pisharath & Shondra M. Pruett-Miller & Sung-Jin Ba, 2024. "NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Xiangyi S. Wang & Thomas R. Cotton & Sarah J. Trevelyan & Lachlan W. Richardson & Wei Ting Lee & John Silke & Bernhard C. Lechtenberg, 2023. "The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Lining Lu & Xiaoguo Zhai & Xiaolong Li & Shuansuo Wang & Lijun Zhang & Luyang Wang & Xi Jin & Lujun Liang & Zhiheng Deng & Zichen Li & Yanfeng Wang & Xiangdong Fu & Honggang Hu & Jiawei Wang & Ziqing , 2022. "Met1-specific motifs conserved in OTUB subfamily of green plants enable rice OTUB1 to hydrolyse Met1 ubiquitin chains," Nature Communications, Nature, vol. 13(1), pages 1-14, 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:12:y:2021:i:1:d:10.1038_s41467-021-25944-2. 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.