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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
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    References listed on IDEAS

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    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.
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    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.

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