PLD3 (Phospholipase D3) is a lysosomal enzyme that, despite its name, functions primarily as a 5'-3' exonuclease rather than a phospholipase. The protein is synthesized as a type II transmembrane glycoprotein and traffics to lysosomes where it is proteolytically cleaved to release its soluble catalytic domain. PLD3 degrades single-stranded DNA and RNA from the 5' end at acidic pH, generating nucleoside 3'-monophosphates. This nuclease activity is critical for degrading mitochondrial DNA and other nucleic acids in lysosomes, thereby preventing inappropriate activation of nucleic acid-sensing innate immune receptors (TLR7, TLR9, cGAS-STING). Recent work (2024) has also established that PLD3 synthesizes (S,S)-bis(monoacylglycero)phosphate (BMP), a key lipid constituent of lysosomal intralumenal vesicles. PLD3 is highly expressed in brain and has been linked to Alzheimer's disease risk (though this remains controversial) and spinocerebellar ataxia type 46 (SCA46).
Definition: Catalysis of the transphosphatidylation reaction between (S,R)-lysophosphatidylglycerol (LPG) and monoacylglycerol (MAG) to yield (S,S)-bis(monoacylglycero)phosphate (BMP).
Justification: A 2024 Cell paper (PMID:39423811) demonstrated that PLD3 and PLD4 synthesize (S,S)-BMP, a key phospholipid in lysosomal intralumenal vesicles. This is a distinct enzymatic activity not well captured by existing GO terms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | ACCEPT | Summary: PLD3 is a type II transmembrane protein that traffics through the ER and Golgi to lysosomes and endosomes, making endomembrane system localization appropriate. The IBA annotation based on phylogenetic inference is consistent with experimental localization data. Reason: PLD3 localizes to ER membrane, Golgi membrane, endosome membrane, and lysosomal lumen - all components of the endomembrane system. This is supported by multiple experimental studies. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 is a type II transmembrane protein whose luminal domain is proteolytically released to form the active soluble lysosomal enzyme file:human/PLD3/PLD3-deep-research-openai.md See deep research file for comprehensive analysis |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: PLD3 traffics through the Golgi en route to lysosomes. Golgi membrane localization is supported by experimental data. Reason: While PLD3 is present in the Golgi during trafficking, its primary functional localization is in lysosomes and endosomes. The Golgi is a transient compartment during biosynthesis rather than the site of its enzymatic function. |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: PLD3 plays a role in innate immune regulation by degrading nucleic acids in lysosomes that would otherwise activate TLR7/9 and cGAS-STING pathways. Loss of PLD3/PLD4 leads to inflammatory disease in mice. Reason: PLD3 degrades ssDNA and ssRNA in lysosomes, limiting TLR9 and TLR7 activation. PLD3 also prevents mtDNA-mediated activation of cGAS-STING signaling. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md By degrading ssDNA/ssRNA, PLD3 limits activation of endolysosomal nucleic-acid sensors (TLR9/TLR7) |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: PLD3 has well-characterized catalytic activity - both 5'-3' exonuclease activity and BMP synthase activity. This is too general but not incorrect. Reason: While accurate, this term is too broad. More specific molecular function terms like "single-stranded DNA 5'-3' DNA exonuclease activity" (GO:0045145) are available and should be preferred. Proposed replacements: single-stranded DNA 5'-3' DNA exonuclease activity |
| GO:0004518 nuclease activity | IEA GO_REF:0000043 | ACCEPT | Summary: PLD3 has nuclease activity, specifically 5'-3' exonuclease activity on ssDNA and ssRNA. This annotation is accurate but could be more specific. Reason: PLD3 functions as a 5'-3' exonuclease on single-stranded nucleic acids. While more specific terms exist, this parent term is accurate and provides useful categorization. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md Multiple studies show PLD3 cleaves ssDNA and ssRNA from the 5' end at acidic pH consistent with the lysosome |
| GO:0004527 exonuclease activity | IEA GO_REF:0000043 | ACCEPT | Summary: PLD3 is a 5'-3' exonuclease. This annotation is accurate and supported by extensive experimental evidence. Reason: PLD3 has been definitively characterized as a 5'-3' exonuclease that cleaves ssDNA and ssRNA from the 5' end. Multiple structural and biochemical studies confirm this activity. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 preferentially degrades short single-stranded nucleic acids in the lysosomal lumen with an acidic pH optimum around ~6.0 |
| GO:0005768 endosome | IEA GO_REF:0000117 | ACCEPT | Summary: PLD3 localizes to endosomes, supported by experimental evidence showing presence on both early and late endosome membranes. Reason: PLD3 is a type II transmembrane protein that traffics through endosomes to lysosomes. Experimental immunofluorescence and biochemical studies confirm endosomal localization. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 encodes phospholipase D3, a type II single-pass transmembrane glycoprotein localized to the endolysosomal system in human cells |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PLD3 is synthesized as a type II transmembrane protein and is present in the ER membrane during biosynthesis and initial glycosylation. Reason: While PLD3 is localized to the ER membrane during synthesis, this is a biosynthetic/transit location. The functional site is lysosomes. |
| GO:0006259 DNA metabolic process | IEA GO_REF:0000108 | ACCEPT | Summary: PLD3 degrades ssDNA in lysosomes, contributing to DNA catabolism. This annotation is appropriate. Reason: PLD3's primary function involves degradation of ssDNA, particularly mitochondrial DNA delivered to lysosomes via mitophagy. This constitutes involvement in DNA metabolic process. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 targets include mitochondrial DNA fragments delivered to lysosomes via mitophagy; PLD3 deficiency leads to lysosomal mtDNA accumulation |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: PLD3 has recently been shown to synthesize (S,S)-BMP, a key lysosomal phospholipid. This supports involvement in lipid metabolic process. Reason: A 2024 Cell paper demonstrated that PLD3 synthesizes (S,S)-bis(monoacylglycero)phosphate (BMP), a transphosphatidylation reaction. PLD3 loss reduces cellular BMP and impairs lysosomal lipid catabolism. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 catalyzes S,S-BMP formation in vitro and in cells, supporting lysosomal lipid degradation |
| GO:0006954 inflammatory response | IEA GO_REF:0000043 | ACCEPT | Summary: PLD3 negatively regulates inflammatory responses by degrading nucleic acids that would otherwise activate inflammatory TLR and cGAS-STING pathways. Reason: Loss of PLD3/PLD4 causes fatal inflammatory disease in mice. PLD3 degrades nucleic acid ligands of TLR7/9 and prevents mtDNA-mediated activation of cGAS-STING inflammatory signaling. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md In PLD3 deficiency, luminal nucleic acids accumulate and can chronically activate TLRs; leakage of mtDNA into cytosol activates cGAS-STING signaling |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: PLD3 localizes to endosome membranes as a type II transmembrane protein during trafficking to lysosomes. Reason: Experimental evidence confirms PLD3 presence on endosome membranes. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 encodes phospholipase D3, a type II single-pass transmembrane glycoprotein localized to the endolysosomal system in human cells |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: PLD3 has hydrolase activity - it hydrolyzes phosphodiester bonds in nucleic acids and catalyzes transphosphatidylation for BMP synthesis. Reason: While accurate, this is a very general term. More specific terms like exonuclease activity are preferred. Proposed replacements: exonuclease activity |
| GO:0031901 early endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: PLD3 localizes to early endosome membrane during its trafficking to lysosomes. Reason: Experimental data supports early endosome membrane localization. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 encodes phospholipase D3, a type II single-pass transmembrane glycoprotein localized to the endolysosomal system in human cells |
| GO:0031902 late endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: PLD3 localizes to late endosome membrane as part of its trafficking pathway to lysosomes. Reason: Experimental data confirms late endosome membrane localization. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 encodes phospholipase D3, a type II single-pass transmembrane glycoprotein localized to the endolysosomal system in human cells |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000044 | ACCEPT | Summary: PLD3's catalytic domain is proteolytically cleaved and released into the lysosomal lumen where it functions as a soluble exonuclease. Reason: PLD3 undergoes proteolytic cleavage releasing its luminal domain as a soluble active enzyme in the lysosomal lumen. This is the primary site of its enzymatic function. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 is synthesized as a type II transmembrane protein and undergoes proteolytic cleavage in lysosomes to generate a soluble luminal enzyme that is catalytically active |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | KEEP AS NON CORE | Summary: PLD3 is reported to interact with proteins based on high-throughput studies. The term "protein binding" is uninformative. Reason: PMID:20195357 is a large-scale mRNA display screen for transcription factor interacting regions. PLD3 was detected as a prey in this high-throughput interactome study. While the interaction may be valid, the term "protein binding" is uninformative without specifying the binding partner. Supporting Evidence: PMID:20195357 We present the first large-scale IR data set obtained using mRNA display for 50 human transcription factors (TFs), including 12 transcription-related proteins. The core data set (966 IRs; 943 PPIs) displays a verification rate of 70%. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Another high-throughput protein interaction study (HuRI). The term "protein binding" is uninformative. Reason: PMID:32296183 describes HuRI, a systematic human binary protein interactome reference map. PLD3 was detected in this high-throughput yeast two-hybrid screen. While the methodology is rigorous, the term "protein binding" provides little functional insight without specifying the interaction partners. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000107 | ACCEPT | Summary: PLD3 is a type II transmembrane protein that localizes to the lysosomal membrane before being proteolytically cleaved. Reason: PLD3 is sorted to lysosomes via ubiquitination and ESCRT machinery. The full-length membrane-bound form is present on lysosomal membrane before cleavage releases the soluble luminal enzyme. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md PLD3 localizes to neurons and is enriched in lysosomes/dystrophic neurites around beta-amyloid plaques in AD brain; neuronal PLD3 co-localizes with LAMP2 and cathepsins |
| GO:0045145 single-stranded DNA 5'-3' DNA exonuclease activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the core molecular function of PLD3. It is a 5'-3' exonuclease that degrades ssDNA. Reason: Extensive structural and biochemical evidence demonstrates PLD3 is a 5'-3' exonuclease on ssDNA. This is now considered its primary enzymatic function (EC 3.1.16.1). Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md A dedicated cell-based assay demonstrated PLD3 as the principal acid 5' exonuclease in HeLa cells |
| GO:1900015 regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | ACCEPT | Summary: PLD3 regulates inflammatory cytokine production by degrading nucleic acids that would otherwise activate TLR and cGAS-STING pathways. Reason: Loss of PLD3/PLD4 leads to overproduction of inflammatory cytokines due to hyperactive TLR9 signaling and cGAS-STING activation. PLD3 negatively regulates cytokine production by eliminating immunostimulatory nucleic acids. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md In PLD3 deficiency, luminal nucleic acids accumulate and can chronically activate TLRs; leakage of mtDNA into cytosol activates cGAS-STING signaling |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: PLD3 localizes to the ER during biosynthesis as a type II transmembrane protein. Reason: ER localization is a biosynthetic/transit compartment for PLD3. The protein ultimately functions in lysosomes. ER localization based on immunofluorescence (GO_REF:0000052) is valid but represents nascent protein. |
| GO:1900015 regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation with ISS evidence. Same term as IEA version. Reason: The annotation is correct - PLD3 regulates inflammatory cytokine production. Multiple evidence sources support this function. Supporting Evidence: file:human/PLD3/PLD3-deep-research-falcon.md By degrading ssDNA/ssRNA, PLD3 limits activation of endolysosomal nucleic-acid sensors (TLR9/TLR7) |
| GO:0000139 Golgi membrane | IDA PMID:29368044 Analysis of novel endosome-to-Golgi retrieval genes reveals ... | KEEP AS NON CORE | Summary: Experimental evidence for Golgi membrane localization from PMID:29368044. Reason: PMID:29368044 demonstrates PLD3 involvement in endosome-to-Golgi retrieval and Golgi localization. However, Golgi is not the primary functional site - lysosomes are. Supporting Evidence: PMID:29368044 Quantitation of the colocalisation of the PLD3-GFP protein with endo/lysosomal- and Golgi-localised proteins including Lamp1, TGN46 and APP confirmed that PLD3-GFP was present in Golgi and post-Golgi membranes in both HeLa and SH-SY5Y cells |
| GO:0014902 myotube differentiation | IDA PMID:22428023 A role for phospholipase D3 in myotube formation. | KEEP AS NON CORE | Summary: PMID:22428023 reports a role for PLD3 in myotube formation in response to ER stress. Reason: This is a specialized function observed in muscle cell differentiation contexts. UniProt notes: "May play a role in myotube formation in response to ER stress." This is not a core function but represents a context-specific role. Supporting Evidence: PMID:22428023 increased PLD3 expression enhances myotube formation, whereas a putatively dominant-negative PLD3 mutant isoform reduces myotube formation. ER stress, which also enhances myotube formation, is shown here to increase PLD3 expression levels. |
| GO:0031901 early endosome membrane | IDA PMID:29386126 Unconventional Trafficking of Mammalian Phospholipase D3 to ... | ACCEPT | Summary: Experimental demonstration of early endosome membrane localization. Reason: PMID:29386126 provides direct experimental evidence for PLD3 localization to early endosome membrane through detailed biochemical and microscopy analyses. Supporting Evidence: PMID:29386126 We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery. |
| GO:0031902 late endosome membrane | IDA PMID:29386126 Unconventional Trafficking of Mammalian Phospholipase D3 to ... | ACCEPT | Summary: Experimental demonstration of late endosome membrane localization. Reason: PMID:29386126 provides direct experimental evidence for PLD3 localization to late endosome membrane through ESCRT-dependent sorting into intraluminal vesicles of multivesicular endosomes. Supporting Evidence: PMID:29386126 PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination. In multivesicular endosomes, PLD3 is subjected to proteolytic cleavage, yielding a stable glycosylated luminal polypeptide and a rapidly degraded N-terminal membrane-bound fragment. |
| GO:0043202 lysosomal lumen | IDA PMID:30312375 PLD3 and spinocerebellar ataxia. | ACCEPT | Summary: Experimental evidence for lysosomal lumen localization of the cleaved, active form of PLD3. Reason: PMID:30312375 demonstrates PLD3 localization and exonuclease activity in lysosomal lumen, clarifying its function as a lysosomal rather than ER-resident enzyme. Supporting Evidence: PMID:30312375 We recently characterized PLD3 as a resident lysosomal protein that is synthesized as a transmembrane protein that undergoes proteolytic cleavage, thereby releasing a stable soluble lysosomal enzyme with 5β² exonuclease activity |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:15794758 Hu-K4 is a ubiquitously expressed type 2 transmembrane prote... | KEEP AS NON CORE | Summary: Initial characterization of PLD3 (Hu-K4) as an ER-associated type II transmembrane protein. Reason: PMID:15794758 first characterized PLD3 as an ER-associated protein. While true for nascent protein, the mature functional form is in lysosomes. Supporting Evidence: PMID:15794758 Using a specific antiserum produced against Hu-K4 we found that Hu-K4 is a membrane-bound protein colocalizing with protein disulfide isomerase, a marker of the endoplasmic reticulum. Glycosylation of Hu-K4 as shown by treatment with peptide N-glycosidase F or tunicamycin indicates that Hu-K4 has a type 2 transmembrane topology. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:22428023 A role for phospholipase D3 in myotube formation. | KEEP AS NON CORE | Summary: Localization to ER-associated vesicles in differentiating myotubes. Reason: PMID:22428023 shows PLD3 localization to ER-associated vesicles specifically in differentiating myotubes. This is a specialized cellular context, not the primary functional localization. Supporting Evidence: PMID:22428023 PLD3 is a type II glycoprotein associated with the endoplasmic reticulum, is expressed in a wide range of tissues and cells, and undergoes dramatic upregulation in neurons and muscle cells during differentiation. |
| GO:0045145 single-stranded DNA 5'-3' DNA exonuclease activity | IDA PMID:30312375 PLD3 and spinocerebellar ataxia. | ACCEPT | Summary: Direct experimental demonstration of 5'-3' exonuclease activity on ssDNA. Reason: PMID:30312375 provides direct experimental evidence of PLD3's 5'-3' exonuclease activity. This is the core molecular function of PLD3. Supporting Evidence: PMID:30312375 We show that PLD3 is not an ER-resident protein and is localized and active in lysosomes acting as a 5β² exonuclease. The PLD3 mutation leads to ER retention and lack of nuclease function. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomics identified PLD3 in exosomes from prostatic secretions. Reason: Detection in exosomes from high-throughput proteomics is consistent with PLD3's presence in the endolysosomal system (exosomes originate from multivesicular bodies). However, this is not a functional localization - the protein functions intracellularly in lysosomes. Supporting Evidence: PMID:23533145 Using expressed prostatic secretions in urine (EPS-urine), exosome preparations were characterized by a shotgun proteomics procedure. In pooled EPS-urine exosome samples, ~900 proteins were detected. |
| GO:0005515 protein binding | IPI PMID:24336208 Rare coding variants in the phospholipase D3 gene confer ris... | KEEP AS NON CORE | Summary: PMID:24336208 reports PLD3 interaction with APP (amyloid precursor protein). Reason: The study reports PLD3-APP interaction but the significance is controversial. Later studies did not find PLD3 affecting APP metabolism in relevant mouse models. The "protein binding" term is also uninformative without specifying the binding partner. Supporting Evidence: PMID:24336208 Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular AΞ²42 and AΞ²40, while knock-down of PLD3 leads to a significant increase in extracellular AΞ²42 and AΞ²40. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: PLD3 detected in parotid gland exosomes by proteomics. Reason: High-throughput detection in exosomes is consistent with endolysosomal localization but does not represent the functional site of the enzyme. Supporting Evidence: PMID:19199708 Using MudPIT (multidimensional protein identification technology) mass spectrometry, we catalogued 491 proteins in the exosome fraction of human parotid saliva. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: PLD3 detected in urinary exosomes by proteomics. Reason: Detection in urinary exosomes from high-throughput proteomics. Consistent with but not the primary functional localization. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously |
| GO:0004630 D-type glycerophospholipase activity | TAS PMID:9140189 A human homolog of the vaccinia virus HindIII K4L gene is a ... | REMOVE | Summary: This annotation is based on the original 1997 study identifying PLD3 as a member of the phospholipase D superfamily. However, subsequent studies have definitively shown that PLD3 does NOT have significant phospholipase D activity and instead functions as a 5'-3' exonuclease. Reason: PMID:9140189 identified PLD3 as having sequence homology to the PLD superfamily, leading to the assumption of phospholipase activity. However, extensive subsequent biochemical studies have definitively demonstrated that PLD3 lacks significant phospholipase D activity and instead functions as a 5'-3' exonuclease. UniProt now classifies PLD3 as EC 3.1.16.1 (5'-3' exonuclease) rather than as a phospholipase. This annotation should be removed as it is now known to be incorrect. Supporting Evidence: PMID:9140189 We have identified a human gene encoding a protein with 48% amino acid identity to the vaccinia virus (VV) K4L gene product. Both contain motifs characteristic of the phospholipase D (PLD) protein superfamily. |
| GO:0016780 phosphotransferase activity, for other substituted phosphate groups | IDA PMID:39423811 PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enablin... | NEW | Summary: PLD3 has been demonstrated to catalyze a transphosphatidylation reaction, synthesizing (S,S)-BMP from LPG and monoacylglycerol substrates. This phosphotransferase activity represents a second core enzymatic function distinct from its exonuclease activity. Reason: A 2024 Cell paper (PMID:39423811) demonstrated that purified PLD3 synthesizes (S,S)-bis(monoacylglycero)phosphate via a transphosphatidylation reaction. This BMP synthase activity is essential for lysosomal lipid catabolism. This molecular function annotation should be added as it represents a newly characterized core enzymatic activity. Supporting Evidence: PMID:39423811 Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. |
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Download this section (compressed HTML)Q: How do the dual enzymatic activities of PLD3 (exonuclease and BMP synthase) relate to each other mechanistically and physiologically? Both activities use the HKD catalytic motifs but act on very different substrates. Understanding their relative contributions to lysosomal function is important.
Q: What is the relative contribution of PLD3 vs PLD4 to immune regulation in different cell types? PLD3 is highly expressed in neurons while PLD4 is more prominent in immune cells. Their redundancy and tissue-specific functions need clarification.
Experiment: Structural studies of PLD3 with BMP pathway substrates to understand the mechanism of transphosphatidylation. Current structures show ssDNA binding. Structures with lipid substrates would clarify how the same active site accommodates both nucleic acids and lipids.
Experiment: Tissue-specific knockout studies to determine cell-type specific functions of PLD3. Understanding the relative importance of PLD3's nuclease vs BMP synthase activities in neurons vs other cell types would clarify disease mechanisms.
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