# Functions of novel phospholipase D proteins in nucleic acid sensing

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $483,750

## Abstract

Project Summary/Abstract
This is a R01 project to study the role of Phospholipase D4 (PLD4) in nucleic acid sensing. Leukocytes
carry conserved sensors for endocytosed DNA and RNA that trigger the production of proinflammatory
cytokines, including type I interferon. The ensuing inflammation can be beneficial for host defense to
microorganisms, viruses, and tumors, but can also be pathogenic, and may thwart the use of potentially
therapeutic oligonucleotides. PLD4 is a lysosomal protein whose function is not understood. Genome-wide
association studies have linked PLD4 to human rheumatoid arthritis and systemic sclerosis. We find that
PLD4-deficient mice have a phenotype similar to the human disease macrophage activation syndrome,
which is mimicked in mice by repeated injections with Toll-like receptor 9 agonists. Here we test the
hypotheses that PLD4 breaks down ingested DNA and RNA and regulates host defense and inflammation
by promoting the destruction nucleic acids and regulating recognition by TLR7, TLR8 (in humans) and
TLR9. We will characterize how PLD4 deficiency promotes a MAS-like phenotype and how deficiencies in
PLD4 or PLD3+PLD4 affect TLR7 and TLR9 responses to specific ligands, leading to altered cytokine
secretion. The possible role of PLD4 in self/nonself discrimination will also be assessed. The long-term goal
of these studies is to understand the basic biology of PLD4, its functions in host defense and inflammation,
and to develop a basis for potential future translational research.

## Key facts

- **NIH application ID:** 10405523
- **Project number:** 5R01AI142945-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DAVID NEMAZEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $483,750
- **Award type:** 5
- **Project period:** 2019-06-14 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405523

## Citation

> US National Institutes of Health, RePORTER application 10405523, Functions of novel phospholipase D proteins in nucleic acid sensing (5R01AI142945-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10405523. Licensed CC0.

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