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

Amanda L. Gavin, Deli Huang, Tanya R. Blane, Therese C. Thinnes, Yusuke Murakami, Ryutaro Fukui, Kensuke Miyake and David Nemazee ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26150-w

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