PLD3 (Phospholipase D Family Member 3) – Function, Processes, and Localization OpenAI o3-deep-research-2025-06-26 136 citations 2025-11-03T23:38:13.119391

PLD3 (Phospholipase D Family Member 3) – Function, Processes, and Localization

Overview and Key Characteristics

PLD3 is a human gene (UniProt ID Q8IV08) encoding a protein of the phospholipase D superfamily. Despite its name, PLD3 is now recognized not as a conventional phospholipase, but as a lysosomal 5′–3′ exonuclease with a critical role in nucleic acid metabolism (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In other words, PLD3 catalyzes the hydrolysis of phosphodiester bonds in single-stranded nucleic acids from their 5′ end, progressively releasing nucleotide fragments. This activity was historically observed as the classic “spleen acid exonuclease” described in the 1960s (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), but the responsible gene remained unknown for decades. It was only in 2018 that PLD3 was identified as the source of this acidic 5′ exonuclease activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The PLD3 protein is highly conserved across mammals (over 90% identical between human, cow, rat, and pig), underscoring its fundamental biological importance (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

PLD3 is broadly expressed in human tissues, with particularly high expression in the brain (pmc.ncbi.nlm.nih.gov). It belongs to a family of six mammalian PLD-like enzymes (PLD1–PLD6) that share a common HxKxxxxD (HKD) catalytic motif (academic.oup.com). Unlike the well-known PLD1 and PLD2 that act as phospholipases hydrolyzing phosphatidylcholine, PLD3’s primary function is nucleolytic. Early predictions and names (e.g. “choline phosphatase 3” or “phosphatidylcholine-hydrolyzing PLD3”) reflected its homology to PLD enzymes (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). However, targeted studies have since shown PLD3 lacks significant phospholipase activity under physiological conditions, and instead cleaves single-stranded DNA and RNA as its main substrate (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Notably, PLD3 can degrade single-stranded RNA with efficiency similar to single-stranded DNA in vitro (academic.oup.com), although DNA appears to be the major physiological substrate in cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Structure and Enzymatic Function

The PLD3 protein is synthesized as a type II transmembrane glycoprotein about 490 amino acids in length (pmc.ncbi.nlm.nih.gov). It contains a short N-terminal segment facing the cytosol, a single transmembrane helix (around residues ~40–60), and a large C-terminal domain (~430 amino acids) that resides within the lumen of the endoplasmic reticulum (ER) and later endo-lysosomal compartments (academic.oup.com) (pmc.ncbi.nlm.nih.gov). The luminal domain harbors two tandem HKD motifs characteristic of PLD-family phosphodiesterases (academic.oup.com). (Notably, the second HKD in PLD3 is slightly variant, H→E, but it still contributes to the active site (academic.oup.com).) Crystal structural studies in 2024 confirmed that the luminal domain of human PLD3 adopts the α/β hydrolase fold typical of PLD enzymes and forms homodimers in solution (academic.oup.com) (academic.oup.com). Each PLD3 dimer presents two independent active centers, and structures of PLD3 bound to single-stranded DNA fragments show catalytic pockets accommodating nucleotides (academic.oup.com) (academic.oup.com). These structural insights support a mechanism in which the conserved histidine of the HKD motif acts on the phosphodiester backbone of nucleic acids, cleaving one nucleotide at a time from the 5′ end (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consistent with this, mutating the critical HKD histidines abolishes PLD3’s nuclease activity (pmc.ncbi.nlm.nih.gov).

Biochemically, PLD3 is a 5′→3′ exonuclease specific for single-stranded nucleic acids. It requires an exposed 5′ terminus to initiate cleavage and has negligible endonuclease or 3′-exonuclease activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Optimal activity occurs in the acidic pH range (around pH 5.0–6.0) (pmc.ncbi.nlm.nih.gov), aligning with the enzyme’s lysosomal locale. In vitro assays show that PLD3 cleavage of oligonucleotides yields mainly 3′ mononucleotides and nucleosides as products (pmc.ncbi.nlm.nih.gov). (This indicates that PLD3 hydrolyzes the phosphodiester bond such that the leaving nucleotide retains its 3′ phosphate, similar to classical spleen phosphodiesterase (pmc.ncbi.nlm.nih.gov).) The enzyme is relatively non-sequence-specific, degrading a wide variety of single-stranded DNA sequences and even RNA, although it shows low efficiency on well-paired double-stranded DNA (pmc.ncbi.nlm.nih.gov). Moreover, PLD3 is reported to be non-processive, meaning it may dissociate after releasing each nucleotide or short fragment, akin to the behavior of the historical spleen exonuclease (pmc.ncbi.nlm.nih.gov). This non-processive nature was deduced from early biochemical characterizations and matches the conserved properties observed for PLD3 and its paralog PLD4 (pmc.ncbi.nlm.nih.gov).

It is worth noting that overexpression studies have occasionally reported low levels of phospholipase activity for PLD3 in cell culture (academic.oup.com). For example, one group observed that transfected PLD3 could hydrolyze a phospholipid substrate in COS-7 cells (academic.oup.com). However, such findings are considered experimental artifacts or overexpression-related effects. Current consensus is that PLD3’s physiologic role is as a nuclease, and it does not significantly contribute to lipid phospholipid metabolism in vivo (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This consensus is supported by genetic and biochemical evidence (see below) and has redefined PLD3’s enzyme classification to EC 3.1.16.1 (5′-3′ exonuclease) (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Localization, Processing, and Regulation

PLD3 follows the secretory pathway and localizes primarily to acidic endosomal and lysosomal compartments within the cell. After translation in the ER, the type II membrane topology of PLD3 positions its large C-terminal domain in the ER lumen, where it undergoes N-linked glycosylation (pmc.ncbi.nlm.nih.gov). (Multiple N-glycosylation sites are present; for example, Asn-97 is a confirmed glycosylation site (glycosmos.org), and others exist throughout the luminal domain.) Glycosylation is important for proper folding and stability, as is typical for lysosomal enzymes. PLD3 then traffics from the Golgi to endo-lysosomes. Unlike soluble lysosomal hydrolases that use mannose-6-phosphate receptors, PLD3’s membrane-bound nature requires a different targeting mechanism. The cytosolic N-terminus of PLD3 is ubiquitinated, which serves as a lysosomal sorting signal (academic.oup.com). Ubiquitinated PLD3 is recognized by the ESCRT machinery and incorporated into the inward budding vesicles of multivesicular bodies, delivering PLD3 into intra-lysosomal vesicles (academic.oup.com).

Within the lysosome, PLD3 undergoes proteolytic cleavage, separating the luminal catalytic domain (~55 kDa) from the membrane anchor (pmc.ncbi.nlm.nih.gov). This cleavage likely occurs via lysosomal proteases after PLD3 is sequestered into intraluminal vesicles, or at the lysosomal membrane, releasing the soluble C-terminal domain into the lysosomal lumen (academic.oup.com) (pmc.ncbi.nlm.nih.gov). The cleaved luminal fragment is the active enzyme that degrades nucleic acids in the lysosome. Experimental evidence shows that PLD3’s luminal domain is quite stable once processed – it remains as a mature enzyme in lysosomes (pmc.ncbi.nlm.nih.gov). Proper processing is crucial: mutations that disrupt PLD3 trafficking or cleavage can lead to mislocalization or an inactive enzyme. For instance, a disease-associated mutant (L308P) was found to misfold and partially lose lysosomal targeting (academic.oup.com), suggesting that correct folding and cleavage are needed for function.

PLD3 is also subject to unusual post-translational regulations. A recent proteomics study (2024) found that PLD3 can be AMPylated (covalently modified by adenylylation) in cells, and this modification impacted its lysosomal processing (pubmed.ncbi.nlm.nih.gov). Specifically, AMPylation of luminal PLD3 was proposed to reduce its proteolytic cleavage, thereby modulating the amount of active enzyme in lysosomes. Such a regulatory mechanism hints that cells can fine-tune PLD3 activity in response to certain signals – for example, during stress or in certain neurodegenerative conditions where AMPylation levels change (pubmed.ncbi.nlm.nih.gov). While the full biological context of PLD3 AMPylation remains to be explored, this finding highlights that PLD3’s function can be dynamically regulated beyond gene expression alone.

In summary, PLD3 is normally localized to lysosomes (and late endosomes) where its active luminal domain encounters nucleic acid substrates. Microscopy studies confirm that PLD3 co-localizes with lysosomal markers (like LAMP2) in cells (academic.oup.com). Notably, in neurons, PLD3 has been observed accumulating in axonal lysosome-related organelles; for example, PLD3 immunostaining is enriched in neuritic plaques in Alzheimer’s disease (AD) brains (pmc.ncbi.nlm.nih.gov). This localization to pathological protein aggregates likely reflects the buildup of lysosomal vesicles in dystrophic neurites, a common feature of neurodegenerative disease. Overall, the spatial context of PLD3’s activity – within the acidic lumen of degradative organelles – is central to its role in cellular homeostasis.

Biological Roles and Pathways

PLD3’s primary biological role is in the degradation of nucleic acids within lysosomes, which is a crucial part of cellular waste management and innate immune regulation. Any DNA or RNA from phagocytosed material, apoptotic cells, organelle turnover (e.g. from mitophagy), or invasive pathogens must be broken down in lysosomes. PLD3, together with other lysosomal nucleases, ensures this degradation is efficient and complete. In particular, PLD3 acts after initial endonucleases have cut nucleic acids into fragments. For instance, lysosomal RNase T2 cleaves single-stranded RNA into oligonucleotides (academic.oup.com), and DNA-specific DNase II (acid DNase) cuts double-stranded DNA internally. PLD3 then processes the resulting fragments by chewing in from the 5′ ends, yielding mononucleotides (pmc.ncbi.nlm.nih.gov). This sequential teamwork of nucleases ensures that nucleic acid debris is fully destroyed. Consistent with this, cells lacking PLD3 show accumulation of short DNA fragments in endolysosomal compartments (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These undigested fragments can have significant consequences: they can escape or be sensed, leading to inappropriate immune activation (see below).

One of the most critical pathways involving PLD3 is the regulation of endosomal Toll-like receptors (TLRs) that detect nucleic acids. TLR9 recognizes unmethylated DNA (often CpG-rich) and TLR7/8 recognize single-stranded RNA in endosomes. In normal conditions, PLD3 helps limit the availability of immunostimulatory DNA and RNA in endosomes by degrading them. Research in Nature Immunology (2018) demonstrated that murine immune cells deficient in PLD3 (and its close paralog PLD4) had impaired turnover of TLR9 ligands and consequently hyperactive TLR9 signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Purified PLD3/PLD4 enzymes were shown to degrade CpG oligodeoxynucleotides (TLR9 agonists) in vitro, especially those without protective modifications, thereby reducing TLR9 activation (pmc.ncbi.nlm.nih.gov). This indicates PLD3 acts as a negative regulator of DNA-sensing TLR pathways: by destroying DNA ligands, it prevents excessive type I interferon and cytokine responses to self-DNA or chronically present DNA. Indeed, mice lacking both Pld3 and Pld4 develop fatal inflammatory disease early in life. Double-knockout pups exhibited severe liver inflammation and overproduction of inflammatory cytokines, dying within weeks of birth (pmc.ncbi.nlm.nih.gov). This lethal phenotype underscores that at least one of these exonucleases is required to keep innate immune sensors quiescent by disposing of nucleic acid by-products. Even single-gene knockouts have immune consequences: Pld4^-/- mice, for example, showed chronic immune activation reminiscent of macrophage activation syndrome (an inflammatory condition) (pmc.ncbi.nlm.nih.gov). These findings firmly establish PLD3 (and PLD4) as part of the cell’s innate immune homeostasis machinery, functionally analogous to intracellular DNA exonucleases like TREX1 (which works in the cytosol) but operating within lysosomes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Recent research has also identified mitochondrial DNA (mtDNA) as a key endogenous substrate of PLD3, linking PLD3 to the cGAS–STING pathway of innate immunity. A 2023 study in Nature Communications found that loss of PLD3 in neuronal cells led to the accumulation of mtDNA inside lysosomes and its leakage into the cytosol (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Normally, mtDNA released by damaged mitochondria is delivered to lysosomes for degradation. In PLD3-deficient cells, mtDNA was not efficiently degraded, resulting in fragments that escaped into the cytoplasm and activated the cGAS-STING pathway – a cytosolic DNA-sensing mechanism that triggers interferon responses (pmc.ncbi.nlm.nih.gov). Activation of STING in those PLD3-deficient neurons drove a stress response that included enhanced autophagy (as the cell attempts to remove the accumulating material) and altered metabolism (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Intriguingly, this study also connected the overactive STING signaling to changes in processing of amyloid precursor protein (APP), suggesting a bridge between nucleic-acid clearance in lysosomes and neurodegenerative pathways (discussed more below). The cGAS-STING activation in PLD3 knockout models could be partially normalized by reintroducing PLD3 or by pharmacologically inhibiting STING, confirming that the effect was due to aberrant DNA persisting and engaging innate sensors (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, PLD3 serves as a guardian in the lysosome, preventing untimely immune activation by degrading self-DNA (such as mtDNA) and probably foreign nucleic acids (e.g. viral genomic DNA/RNA) that end up in lysosomes during infections.

Beyond immune regulation, PLD3’s nucleolytic function is generally important for cellular clearance processes. For example, during autophagy, cellular components (including nuclei or organelles) are delivered to lysosomes; nucleic acids therein must be broken down. PLD3 deficiency has been associated with defective degradation in autolysosomes, leading to secondary issues like buildup of undigested material. The loss of PLD3 (along with PLD4) in mice causes accumulation of undegraded lysosomal DNA/RNA which continuously stimulates immune sensors, indicating a failure of complete clearance (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). There is also evidence that PLD3 dysfunction can perturb lipid metabolism in lysosomes. Van Acker et al. (2023) observed that human cell models lacking PLD3 had 2–3× higher lysosomal storage lipid accumulation compared to normal cells (pmc.ncbi.nlm.nih.gov). This was attributed to broad lysosomal dyshomeostasis: the backlogged nucleic acids and chronic STING activation might impair lysosome function or gene expression programs (like cholesterol metabolism pathways) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Indeed, PLD3-deficient cells showed changes in cholesterol processing and in the activity of SREBP2 (a cholesterol regulator), linking PLD3 indirectly to lipid homeostasis via lysosomal function (pmc.ncbi.nlm.nih.gov). While the primary role of PLD3 is nucleic acid catabolism, these observations illustrate how its loss can have pleiotropic downstream effects on cellular physiology – reflecting the central role of lysosomes in many metabolic and signaling networks.

Connections to Human Disease and Clinical Insights

Alzheimer’s Disease (AD): PLD3 came to prominence in 2014 when a rare coding variant in PLD3 was reported to be associated with a doubled risk of late-onset Alzheimer’s disease (academic.oup.com). The variant (a missense mutation Val232Met, V232M) was initially found in AD patients more frequently than in healthy elderly controls, and carriers showed worse memory performance (pmc.ncbi.nlm.nih.gov). This discovery prompted intense interest in PLD3 as a potential AD-related gene. However, subsequent genetic studies yielded mixed results – several groups failed to replicate a significant association of common PLD3 variants with AD risk (academic.oup.com). A 2018 meta-analysis concluded that PLD3 variants have at most a modest effect on AD risk (academic.oup.com). The initial risk finding is now viewed as controversial, and some researchers suggest the early results may have been confounded by strong overexpression artifacts in cellular models rather than true genetic causation (academic.oup.com). In essence, the role of PLD3 in AD predisposition remains unproven, and it is not considered a major genetic risk factor at present.

That said, biological studies continue to support a link between PLD3 and AD-related processes. PLD3 is highly expressed in neurons, and its protein product localizes to neuronal lysosomes, which are critical sites for APP processing and Aβ peptide generation (pmc.ncbi.nlm.nih.gov). It has been observed that PLD3 levels are altered in AD brains and that PLD3 accumulates around β-amyloid plaques in the brain (pmc.ncbi.nlm.nih.gov). Experimental overexpression of PLD3 in cell and animal models was reported to reduce levels of full-length APP and Aβ peptides, whereas PLD3 knockdown or loss led to increased Aβ production (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These effects hint that PLD3 might influence how APP is trafficked or degraded in the endolysosomal pathway. The 2023 Nature Communications study provided a more refined explanation: loss of PLD3 causes chronic STING activation and lysosomal stress, which in turn can alter APP metabolism. In PLD3 knockout neuronal cells, the accumulation of APP C-terminal fragments (APP-CTFs, the direct precursors to Aβ) was observed, alongside elevated secretion of Aβ40/42 peptides (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This accumulation was tied to impaired autophagic clearance – essentially, overloaded lysosomes and high STING activity slowed the turnover of APP fragments (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Notably, when STING signaling was pharmacologically inhibited in these PLD3-deficient cells, the abnormal buildup of APP-CTFs was largely rescued (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Furthermore, genetic removal of APP itself in the PLD3-deficient background reduced the excessive autophagy and lysosomal disruptions (pmc.ncbi.nlm.nih.gov), indicating a two-way interplay. These findings outline a novel pathogenic feedback loop: PLD3 dysfunction → mtDNA escape and STING activation → lysosome-autophagy dysfunction → altered APP/Aβ metabolism, which could exacerbate neuronal damage in AD (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). While this is an emerging hypothesis, it aligns with the broader view that endolysosomal health and innate immune activation are important in late-onset AD. Thus, even if PLD3 variants are not a major cause of AD, PLD3 activity (or lack thereof) may influence disease progression or severity by modulating these cellular pathways.

Neurodegeneration and Ataxia: Apart from AD, PLD3 has been investigated in other neurological disorders. A rare mutation in PLD3 (e.g. L308P) was reported in a family with spinocerebellar ataxia (SCA46), suggesting PLD3 as a candidate gene for this dominantly inherited ataxia (academic.oup.com). The proposed mechanism was that this mutation caused PLD3 loss-of-function, leading to neurodegeneration in cerebellar neurons. However, the link between PLD3 and SCA46 is still under debate. Subsequent analyses did not find PLD3 mutations in other SCA patients, and the original family’s genome had other potential culprit genes (academic.oup.com). Researchers pointed out that the L308P variant disrupts PLD3’s normal lysosomal localization and stability (academic.oup.com), which could conceivably contribute to neuronal dysfunction; but definitive proof of causation is lacking. As of 2023, PLD3 is not firmly established as an ataxia gene, though it remains of interest and further cases are being studied to clarify this link (academic.oup.com). What the ataxia report did highlight is that neurons (particularly Purkinje cells in the cerebellum) may be vulnerable to disruptions in lysosomal nucleic acid clearance. If PLD3 function is compromised, accumulating nucleic acids or the resulting inflammation could impair neuronal homeostasis over time.

Autoimmune Disease: Given PLD3’s role in restraining nucleic acid–triggered innate immunity, it is plausible that variations in PLD3 could impact susceptibility to autoimmune or inflammatory diseases. To date, strong human genetic links have been seen with its paralog PLD4 – certain PLD4 variants are associated with systemic lupus erythematosus and rheumatoid arthritis (academic.oup.com). For PLD3, no common variant with a large effect has been definitively tied to autoimmunity, but research is ongoing. One study noted that PLD3 is broadly expressed (including in some immune cells), so it may compensate for PLD4 except in certain contexts (academic.oup.com). In mouse models, as mentioned, the absence of PLD3/4 leads to interferon-driven inflammation resembling autoimmune syndromes, reinforcing the idea that defects in lysosomal nucleic acid processing can precipitate autoimmune pathology (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

From a clinical perspective, PLD3’s involvement in these pathways makes it an intriguing therapeutic target or biomarker. For example, boosting PLD3 activity might help “clean up” DNA in conditions where auto-reactive inflammation is a problem (like lupus or Aicardi-Goutières syndrome, which involve DNA sensing). Conversely, inhibiting PLD3 in a controlled way could potentially enhance vaccine responses or anti-tumor immunity by allowing more DNA-based activation of TLR9/STING – though with the risk of inflammation. As of now, no drugs specifically target PLD3, but experts have suggested that modulating PLD3 could be immunomodulatory (academic.oup.com) (academic.oup.com). The recent structural resolution of PLD3 may facilitate structure-guided design of small molecules that adjust its activity (academic.oup.com) (academic.oup.com). Additionally, PLD3 levels or mutation status might serve as a biomarker in neurodegenerative disease research. For instance, reduced PLD3 expression or activity could indicate a propensity for accumulation of lysosomal DNA and ensuing neuroinflammation, potentially correlating with disease progression in AD (some studies have reported epigenetic changes reducing PLD3 expression in AD brains (pmc.ncbi.nlm.nih.gov)).

Expert Commentary and Future Directions

Researchers now broadly view PLD3 as a lysosomal “housekeeping” enzyme that safeguards cellular homeostasis. The discovery of its nuclease function answered a long-standing question about the identity of acidic spleen exonuclease (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Expert opinions emphasize that PLD3 (and PLD4) form an important parallel to other nucleic acid control mechanisms (like TREX1 in the cytosol or DNase II in lysosomes) to prevent harmful accumulation of DNA/RNA. As immunologist Kate Fitzgerald commented in 2018, the fact that Pld3/4 double-knockout mice succumb to inflammatory disease underscores how crucial this pathway is to avoid self-DNA sensing (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Immunology experts have noted that these findings broaden our understanding of innate immunity, revealing the lysosome as not just a degradation center but also a regulatory hub where insufficient degradation can tip off immune receptors (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Neurologists studying Alzheimer’s disease have also taken interest. While the genetic link between PLD3 and AD is debated (academic.oup.com), (academic.oup.com), neurobiologists like R. Cruchaga (who first reported the PLD3-AD variant) suggest that even if PLD3 variants are rare, the lysosomal processes it participates in are likely part of AD pathology (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The latest research supports a view that age-related decline in lysosomal nuclease function or minor inherited reductions in PLD3 activity could contribute to late-life proteinopathies by aggravating inflammation and proteostasis defects (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This aligns with a growing consensus that enhancement of lysosomal function is broadly beneficial in neurodegenerative diseases. Some experts speculate that upregulating PLD3 (for instance via small molecules or gene therapy) in the brain might improve clearance of neuronal waste and mitigate neuroinflammation, though this remains to be tested.

On the structural biology front, scientists Aleksandar Bijelić and Peter Macheroux (who published one of the 2024 PLD3 structures) highlighted that the enzyme’s dimeric arrangement and substrate-bound conformation provide “a molecular basis for understanding its normal and pathological functions” (pmc.ncbi.nlm.nih.gov) (academic.oup.com). Important questions for the future include determining how PLD3 selects its substrates (e.g. any preference for DNA vs RNA or sequence motifs), and how it cooperates with other lysosomal nucleases. There is also interest in discovering regulatory partners: for example, does PLD3 interact with lysosomal membrane proteins or require cofactors for full activity? The newly observed AMPylation modification points to regulatory crosstalk with cellular signaling pathways (pubmed.ncbi.nlm.nih.gov). Since AMPylation often occurs under ER stress or in specific developmental contexts, it raises the possibility that PLD3’s activity could be dialed down when cells are under stress, perhaps to prioritize other pathways or due to changes in lysosomal pH.

In conclusion, PLD3 serves as a critical lysosomal nuclease, maintaining a balance between waste degradation and immune surveillance. It illustrates how finely tuned our cells must be in handling self-DNA: too little cleanup can trigger inflammation, while proper function prevents unwarranted immune responses. Ongoing research in 2023–2024 has not only clarified PLD3’s enzymatic function and 3D structure, but also connected it to complex disease pathways in neurodegeneration and immunity. As we advance, targeting the PLD3 pathway could emerge as a novel strategy to modulate innate immunity or to bolster lysosomal health in age-related diseases. The precise role of PLD3 in human health and disease will be further illuminated by future studies, but it is already clear that this once-mysterious “phospholipase D” family member is, in reality, an essential nuclease at the intersection of metabolism, immunity, and neurobiology.

References:

  1. Gavin AL et al. (2018). Nat. Immunol. 19(9):942–953. DOI: 10.1038/s41590-018-0179-y — Identified PLD3 and PLD4 as lysosomal 5′ exonucleases that degrade nucleic acids and regulate TLR9 signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  2. Roske Y et al. (2024). Nucleic Acids Res. 52(1):370–384. DOI: 10.1093/nar/gkad1135 — Reported crystal structures of human PLD3, confirming its dimeric phosphodiesterase fold and ssDNA-bound active site (academic.oup.com) (academic.oup.com).
  3. Van Acker ZP et al. (2023). Nat. Commun. 14:2847 (24 May 2023). DOI: 10.1038/s41467-023-38501-w — Demonstrated that PLD3 degrades mitochondrial DNA, linking PLD3 loss to cGAS-STING activation and altered APP (amyloid precursor protein) processing (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  4. Cruchaga C et al. (2014). Nature 513(7518):436–440. DOI: 10.1038/nature13725 — Initial report of a PLD3 V232M variant associated with increased risk of Alzheimer’s disease (academic.oup.com) (subsequent studies provided mixed evidence (academic.oup.com)).
  5. Gonzalez AC et al. (2018). Brain 141(11):e78. DOI: 10.1093/brain/awy252 — Discussion on PLD3 in spinocerebellar ataxia (SCA46), highlighting lysosomal enzyme function and debating causality of PLD3 mutations in ataxia (academic.oup.com) (academic.oup.com).

Citations

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  9. AnnotationURLCitation(end_index=2369, start_index=2218, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=match%20at%20L80%20regulation,is%20highly%20expressed%20in%20brain')
  10. AnnotationURLCitation(end_index=2669, start_index=2495, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=5%E2%80%B2%20exonucleases%20PLD3%20or%20PLD4,linear%20sequences%20containing%20the%20amino')
  11. AnnotationURLCitation(end_index=3072, start_index=2946, title='PLD3 phospholipase D family member 3 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/23646#:~:text=Names%20%28S%2CS%29,hydrolyzing%20phospholipase%20D3')
  12. AnnotationURLCitation(end_index=3191, start_index=3073, title='PLD3 phospholipase D family member 3 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/23646#:~:text=%28S%2CS%29,hydrolyzing%20phospholipase%20D3')
  13. AnnotationURLCitation(end_index=3533, start_index=3392, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=but%20not%203%E2%80%B2,ends%20and%20was%20unaffected%20by')
  14. AnnotationURLCitation(end_index=3653, start_index=3534, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  15. AnnotationURLCitation(end_index=3943, start_index=3757, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=%E2%80%98spleen%20exonuclease%E2%80%99%20was%20identified%20as,fact%2C%20PLD3%20cleaves%20ssRNA%20with')
  16. AnnotationURLCitation(end_index=4141, start_index=4015, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=match%20at%20L225%20from%20PLD3,We%20next')
  17. AnnotationURLCitation(end_index=4248, start_index=4142, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=from%20PLD3,We%20next')
  18. AnnotationURLCitation(end_index=4573, start_index=4398, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  19. AnnotationURLCitation(end_index=5004, start_index=4840, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=similar%20high%20efficiency%20to%20ssDNA,type%20II%20topology%20determines%20the')
  20. AnnotationURLCitation(end_index=5180, start_index=5005, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  21. AnnotationURLCitation(end_index=5453, start_index=5279, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=5%E2%80%B2%20exonucleases%20PLD3%20or%20PLD4,linear%20sequences%20containing%20the%20amino')
  22. AnnotationURLCitation(end_index=5726, start_index=5558, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=biochemical%20mechanism%20and%20an%20H,linear%20sequences%20containing%20the%20amino')
  23. AnnotationURLCitation(end_index=6066, start_index=5910, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=domain%20of%20human%20PLD3%20in,in%20the%20catalytic%20center%20provides')
  24. AnnotationURLCitation(end_index=6223, start_index=6067, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=domain%20of%20human%20PLD3%20in,in%20the%20catalytic%20center%20provides')
  25. AnnotationURLCitation(end_index=6549, start_index=6393, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=domain%20of%20human%20PLD3%20in,in%20the%20catalytic%20center%20provides')
  26. AnnotationURLCitation(end_index=6718, start_index=6550, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=domain%20of%20PLD3%20as%20an,designing%20immunomodulatory%20drugs%20targeting%20PLD3')
  27. AnnotationURLCitation(end_index=7061, start_index=6920, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=but%20not%203%E2%80%B2,ends%20and%20was%20unaffected%20by')
  28. AnnotationURLCitation(end_index=7181, start_index=7062, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  29. AnnotationURLCitation(end_index=7425, start_index=7277, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L232%20but%20not,ends%20and%20was%20unaffected%20by')
  30. AnnotationURLCitation(end_index=7785, start_index=7637, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L232%20but%20not,ends%20and%20was%20unaffected%20by')
  31. AnnotationURLCitation(end_index=7905, start_index=7786, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  32. AnnotationURLCitation(end_index=8154, start_index=7974, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=spleen%20phosphodiesterase%20II%20%28spleen%20exonuclease%29,and%20PLD4%20are%20abbreviated%20as')
  33. AnnotationURLCitation(end_index=8445, start_index=8326, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  34. AnnotationURLCitation(end_index=8732, start_index=8613, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  35. AnnotationURLCitation(end_index=9082, start_index=8923, title='Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7857491/#:~:text=lysosomal%20nuclease%20PLD3%20by%20a,This%20enzyme%20was%20later%20assigned')
  36. AnnotationURLCitation(end_index=9396, start_index=9272, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=We%20find%20that%20PLD3%20and,processive')
  37. AnnotationURLCitation(end_index=9678, start_index=9554, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=We%20find%20that%20PLD3%20and,processive')
  38. AnnotationURLCitation(end_index=9964, start_index=9818, title='Reply: PLD3 and spinocerebellar ataxia | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/141/11/e79/5127750#:~:text=Reply%3A%20PLD3%20and%20spinocerebellar%20ataxia,7%20cells')
  39. AnnotationURLCitation(end_index=10222, start_index=10076, title='Reply: PLD3 and spinocerebellar ataxia | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/141/11/e79/5127750#:~:text=Reply%3A%20PLD3%20and%20spinocerebellar%20ataxia,7%20cells')
  40. AnnotationURLCitation(end_index=10654, start_index=10474, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=were%20presumed%20to%20be%20phospholipases%2C,required%20to%20regulate%20inflammatory%20cytokine')
  41. AnnotationURLCitation(end_index=10796, start_index=10655, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=but%20not%203%E2%80%B2,ends%20and%20was%20unaffected%20by')
  42. AnnotationURLCitation(end_index=11078, start_index=10956, title='PLD3 phospholipase D family member 3 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/23646#:~:text=hindIII%20K4L%20homolog%20phosphatidylcholine,D3')
  43. AnnotationURLCitation(end_index=11242, start_index=11079, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=the%20activity%20previously%20described%20as,a%20positive%20control%20using%20a')
  44. AnnotationURLCitation(end_index=11762, start_index=11587, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  45. AnnotationURLCitation(end_index=11961, start_index=11863, title='GlyCosmos Portal', type='url_citation', url='https://glycosmos.org/glycoproteins/Q8IV08#:~:text=GlyCosmos%20Portal%20,linked')
  46. AnnotationURLCitation(end_index=12542, start_index=12408, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=match%20at%20L381%20lysosome,This%20genetic%20link')
  47. AnnotationURLCitation(end_index=12856, start_index=12722, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=match%20at%20L381%20lysosome,This%20genetic%20link')
  48. AnnotationURLCitation(end_index=13176, start_index=13001, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  49. AnnotationURLCitation(end_index=13541, start_index=13383, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=match%20at%20L376%20similar%20high,type%20II%20topology%20determines%20the')
  50. AnnotationURLCitation(end_index=13717, start_index=13542, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  51. AnnotationURLCitation(end_index=14124, start_index=13949, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=variants%2C%20including%20M6R%2C%20K228R%2C%20V232M%2C,considered%20to%20be%20the%20mature')
  52. AnnotationURLCitation(end_index=14507, start_index=14369, title='PLD3 and spinocerebellar ataxia | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/141/11/e78/5127752#:~:text=Nibbeling%20et%20al.%20used%20GFP,mutant%20protein')
  53. AnnotationURLCitation(end_index=14997, start_index=14824, title="AMPylation Regulates 5'-3' Exonuclease PLD3 Processing - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40816421/#:~:text=Keywords%3A%20AMPylation%3B%20PLD3%3B%20chemical%20proteomics%3B,translational%20modifications')
  54. AnnotationURLCitation(end_index=15468, start_index=15361, title="AMPylation Regulates 5'-3' Exonuclease PLD3 Processing - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40816421/#:~:text=neurodegenerative%20diseases')
  55. AnnotationURLCitation(end_index=16083, start_index=15897, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=%E2%80%98spleen%20exonuclease%E2%80%99%20was%20identified%20as,fact%2C%20PLD3%20cleaves%20ssRNA%20with')
  56. AnnotationURLCitation(end_index=16457, start_index=16289, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=dysregulated%20APP%20processing%20and%20an,27%2C37%7D.%20In%20contrast%2C%20however')
  57. AnnotationURLCitation(end_index=17612, start_index=17426, title='Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/52/1/370/7442542#:~:text=%E2%80%98spleen%20exonuclease%E2%80%99%20was%20identified%20as,fact%2C%20PLD3%20cleaves%20ssRNA%20with')
  58. AnnotationURLCitation(end_index=17910, start_index=17791, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L280%20exonuclease,The')
  59. AnnotationURLCitation(end_index=18249, start_index=18123, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=match%20at%20L225%20from%20PLD3,We%20next')
  60. AnnotationURLCitation(end_index=18356, start_index=18250, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=from%20PLD3,We%20next')
  61. AnnotationURLCitation(end_index=19258, start_index=19089, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=deficient%20in%20both%20PLD3%20and,required%20to%20regulate%20inflammatory%20cytokine')
  62. AnnotationURLCitation(end_index=19404, start_index=19259, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L443%20%28Fig,similar%20in%20human%20and%20mouse')
  63. AnnotationURLCitation(end_index=19746, start_index=19595, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=PLD3%20and%20PLD4%20can%20degrade,agonists%20of%20TLR9%20in%20vitro')
  64. AnnotationURLCitation(end_index=20361, start_index=20181, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=were%20presumed%20to%20be%20phospholipases%2C,required%20to%20regulate%20inflammatory%20cytokine')
  65. AnnotationURLCitation(end_index=20850, start_index=20721, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=Trex1%20exonuclease%20in%20the%20cytoplasm,42')
  66. AnnotationURLCitation(end_index=21216, start_index=21091, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=%28Fig,similar%20in%20human%20and%20mouse')
  67. AnnotationURLCitation(end_index=21346, start_index=21217, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=Trex1%20exonuclease%20in%20the%20cytoplasm,42')
  68. AnnotationURLCitation(end_index=21812, start_index=21678, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=PLD3,an%20altered%20PLD3%20exonuclease%20activity')
  69. AnnotationURLCitation(end_index=21965, start_index=21813, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=activator%20of%20STING,an%20altered%20PLD3%20exonuclease%20activity')
  70. AnnotationURLCitation(end_index=22421, start_index=22287, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=PLD3,an%20altered%20PLD3%20exonuclease%20activity')
  71. AnnotationURLCitation(end_index=22738, start_index=22614, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=amyloid%20precursor%20C,talks%20through')
  72. AnnotationURLCitation(end_index=22877, start_index=22739, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=,reminiscent%20features%20of%20AD%20neuropathogenesis')
  73. AnnotationURLCitation(end_index=23509, start_index=23370, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=match%20at%20L39%20amyloid%20precursor,talks%20through')
  74. AnnotationURLCitation(end_index=23637, start_index=23510, title='Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10209153/#:~:text=cGAS,dysfunction%20with%20APP%20metabolism')
  75. AnnotationURLCitation(end_index=24622, start_index=24483, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=expressed,and%20diminished%20turnover%20of%2C%20ligands')
  76. AnnotationURLCitation(end_index=24768, start_index=24623, title='PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6105523/#:~:text=match%20at%20L443%20%28Fig,similar%20in%20human%20and%20mouse')
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