Related Experiment Video

Updated: Oct 17, 2025

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
09:04

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

21.1K

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

Amanda L Gavin1, Deli Huang1, Tanya R Blane1

  • 1The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.

Nature Communications
|October 8, 2021
PubMed

Insights

Phospholipase D3 (PLD3) and PLD4 enzymes degrade nucleic acids. Their deficiency causes fatal hemophagocytic lymphohistiocytosis (HLH) by activating inflammatory nucleic acid sensing pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Phospholipase D3 (PLD3) and PLD4 gene variants are linked to inflammatory diseases.
  • Previous studies indicated PLD3 and PLD4 interact with DNA.

Purpose of the Study:

  • To investigate the function of PLD3 and PLD4 in nucleic acid metabolism and inflammatory responses.
  • To elucidate the role of PLD3 and PLD4 in the pathogenesis of hemophagocytic lymphohistiocytosis (HLH).

Main Methods:

  • Generation and analysis of Pld3-/-Pld4-/- mice.
  • Assessment of nucleic acid accumulation and inflammatory markers.
  • Evaluation of Toll-like receptor (TLR) and STING pathway involvement.
  • Genetic and antibody-mediated blockade of TLRs.

Main Results:

  • PLD3 and PLD4 were found to degrade both ssRNA and ssDNA.
  • Pld3-/-Pld4-/- mice developed spontaneous, fatal HLH with liver inflammation and high Interferon (IFN)-γ levels.
  • Absence of endosomal TLR signaling rescued pathology, indicating TLR activation by nucleic acids.
  • STING pathway was implicated in remaining inflammatory perturbations.

Conclusions:

  • PLD3 and PLD4 are crucial regulators of both endosomal TLR and cytoplasmic nucleic acid sensing pathways.
  • Dysregulation of PLD3/PLD4 contributes to inflammatory diseases via aberrant nucleic acid sensing.
  • Targeting these pathways may offer therapeutic strategies for nucleic acid-driven inflammatory conditions.

More Related Videos

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages06:52

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages

Published on: May 21, 2018

10.9K
Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.4K

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.5K
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.0K
Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
10.3K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
36.6K
piRNA - Piwi-interacting RNAs02:57

piRNA - Piwi-interacting RNAs

PIWI-interacting RNAs, or piRNAs, are the most abundant short non-coding RNAs. More than 20,000 genes have been found in humans that code for piRNAs while only 2000 genes have been found for miRNAs. piRNAs can act at the transcriptional and post-transcriptional levels and have a vital role in silencing transposable elements present in germ cells. They are also involved in epigenetic silencing and activation. Previously, they were thought to function only in germ cells but new evidence suggests...
7.1K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.1K