ArticleNucleic acids research2024
Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Targeting PLD3 Reverses the Immunosuppressive Niche by Reprogramming Tumor-Associated Macrophages and Potentiates Antitumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PLD3-mediated Mitophagy Attenuates Neuronal Ferroptosis and Promotes Functional Recovery after Spinal Cord Injury.Molecular neurobiology · 2026Article
- Mechanistic insights into single-stranded DNA degradation by lysosomal exonucleases PLD3 and PLD4 from structural snapshots.Nature communications · 2025Article
- The lysosomal catabolism of nucleic acids-critical regulators of the innate immune system.Nucleic acids research · 2025Review
- Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation.bioRxiv : the preprint server for biology · 2025Article
- Structural insights into tecovirimat antiviral activity and poxvirus resistance.Nature microbiology · 2025Article
- Structure of human phospholipase D3, a single-strand exonuclease associated with Alzheimer's disease.The FEBS journal · 2024Article
- Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions.The FEBS journal · 2024Article
- PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.Cell · 2024Article
- Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation.Immunity · 2024Article
- Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4.Structure (London, England : 1993) · 2024Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The phospholipase D (PLD) family is comprised of enzymes bearing phospholipase activity towards lipids or endo- and exonuclease activity towards nucleic acids. PLD3 is synthesized as a type II transmembrane protein and proteolytically cleaved in lysosomes, yielding a soluble active form. The deficiency of PLD3 leads to the slowed degradation of nucleic acids in lysosomes and chronic activation of nucleic acid-specific intracellular toll-like receptors. While the mechanism of PLD phospholipase activity has been extensively characterized, not much is known about how PLDs bind and hydrolyze nucleic acids. Here, we determined the high-resolution crystal structure of the luminal N-glycosylated domain of human PLD3 in its apo- and single-stranded DNA-bound forms. PLD3 has a typical phospholipase fold and forms homodimers with two independent catalytic centers via a newly identified dimerization interface. The structure of PLD3 in complex with an ssDNA-derived thymidine product in the catalytic center provides insights into the substrate binding mode of nucleic acids in the PLD family. Our structural data suggest a mechanism for substrate binding and nuclease activity in the PLD family and provide the structural basis to design immunomodulatory drugs targeting PLD3.
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