IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26150-w.html
   My bibliography  Save this article

Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

Author

Listed:
  • Amanda L. Gavin

    (The Scripps Research Institute)

  • Deli Huang

    (The Scripps Research Institute)

  • Tanya R. Blane

    (The Scripps Research Institute)

  • Therese C. Thinnes

    (The Scripps Research Institute)

  • Yusuke Murakami

    (Laboratory of Pharmacotherapy, Faculty of Pharmacy, Musashino University)

  • Ryutaro Fukui

    (The Institute of Medical Science, The University of Tokyo)

  • Kensuke Miyake

    (The Institute of Medical Science, The University of Tokyo)

  • David Nemazee

    (The Scripps Research Institute)

Abstract

Phospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.

Suggested Citation

  • Amanda L. Gavin & Deli Huang & Tanya R. Blane & Therese C. Thinnes & Yusuke Murakami & Ryutaro Fukui & Kensuke Miyake & David Nemazee, 2021. "Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26150-w
    DOI: 10.1038/s41467-021-26150-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26150-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26150-w?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. Carlos Cruchaga & Celeste M. Karch & Sheng Chih Jin & Bruno A. Benitez & Yefei Cai & Rita Guerreiro & Oscar Harari & Joanne Norton & John Budde & Sarah Bertelsen & Amanda T. Jeng & Breanna Cooper & Ta, 2014. "Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease," Nature, Nature, vol. 505(7484), pages 550-554, January.
    2. Jelka Pohar & Duško Lainšček & Karolina Ivičak-Kocjan & Miša-Mojca Cajnko & Roman Jerala & Mojca Benčina, 2017. "Short single-stranded DNA degradation products augment the activation of Toll-like receptor 9," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    3. Pietro Fazzari & Katrien Horre & Amaia M. Arranz & Carlo Sala Frigerio & Takashi Saito & Takaomi C. Saido & Bart De Strooper, 2017. "PLD3 gene and processing of APP," Nature, Nature, vol. 541(7638), pages 1-2, January.
    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. Zoë P. Van Acker & Anika Perdok & Ruben Hellemans & Katherine North & Inge Vorsters & Cedric Cappel & Jonas Dehairs & Johannes V. Swinnen & Ragna Sannerud & Marine Bretou & Markus Damme & Wim Annaert, 2023. "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, 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. Zoë P. Van Acker & Anika Perdok & Ruben Hellemans & Katherine North & Inge Vorsters & Cedric Cappel & Jonas Dehairs & Johannes V. Swinnen & Ragna Sannerud & Marine Bretou & Markus Damme & Wim Annaert, 2023. "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, 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_s41467-021-26150-w. 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.