PLD4 (Phospholipase D Family Member 4) – Overview and Function OpenAI o3-deep-research-2025-06-26 95 citations 2025-11-03T23:37:57.616746

PLD4 (Phospholipase D Family Member 4) – Overview and Function

Family Context and Structure

PLD4 (gene ID 122618, UniProt Q96BZ4) is a member of the phospholipase D superfamily, which is characterized by a conserved catalytic HKD motif (His-x-Lys-xxxx-Asp) important for phosphodiester bond hydrolysis (pmc.ncbi.nlm.nih.gov). Unlike classical PLD1/PLD2 enzymes (which hydrolyze phosphatidylcholine to choline and phosphatidic acid), PLD4 is a non-classical PLD that lacks the N-terminal PX and PH domains used for membrane targeting in PLD1/2 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Instead, PLD4 has a short N-terminal cytosolic tail, a single transmembrane segment, and a large C-terminal domain with multiple N-glycosylation sites (pmc.ncbi.nlm.nih.gov). Glycosylation and biochemical analyses confirm that PLD4 is a type II membrane glycoprotein localized to the endolysosomal system (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In cells, PLD4 resides in late endosomes/lysosomes – subcellular compartments distinct from where PLD1/2 operate (pmc.ncbi.nlm.nih.gov). Early studies noted PLD4’s absence of classical PLD lipid-hydrolyzing activity, as it failed to convert phosphatidylcholine to phosphatidic acid in enzyme assays (pmc.ncbi.nlm.nih.gov). This suggested that despite its name, PLD4’s biochemical function differs fundamentally from the lipid-degrading activity of PLD1/2 (pmc.ncbi.nlm.nih.gov). Indeed, PLD4 also lacks the regulatory loops present in PLD1/2, consistent with a divergent function and localization.

Structurally, PLD4’s C-terminal domain contains two HKD motifs that fold into an intramolecular “pseudo-dimer” – a hallmark of PLD-family enzymes (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). A recent 2023 structural analysis (bioRxiv preprint, later published 2024) resolved the crystal structure of human PLD4, revealing that its two HKD regions form a single active site at their interface (pmc.ncbi.nlm.nih.gov). The active site is highly basic and binds nucleic acid substrates, rather than phospholipids (pmc.ncbi.nlm.nih.gov). Notably, PLD4 was found to harbor an extra hydrophobic clamp near the active site, which may influence substrate binding and product release (pmc.ncbi.nlm.nih.gov). Like other HKD enzymes (e.g. bacterial nucleases), PLD4’s catalytic mechanism proceeds via a two-step reaction: the enzyme first forms a covalent phosphohistidine intermediate by cleaving the 5′-phosphate from the substrate, then releases inorganic phosphate and continues degrading the nucleic acid (pmc.ncbi.nlm.nih.gov). This “link-and-release” mechanism endows PLD4 with a 5′-phosphatase activity in addition to its primary nuclease function (pmc.ncbi.nlm.nih.gov). In sum, PLD4’s sequence and structure place it in the PLD superfamily, but its domain architecture and active site adaptations are specialized for nucleic-acid substrate binding in the acidic endolysosomal milieu, rather than for lipid metabolism (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Enzymatic Activity and Substrate Specificity

Current understanding indicates that PLD4 is not a phospholipid hydrolase at all, but rather a 5′→3′ exonuclease that digests nucleic acids. Pioneering work in 2018 (Nature Immunology) showed definitively that PLD4 (and the related PLD3) can cleave single-stranded DNA in vitro, and suggested these enzymes correspond to the long-mysterious “spleen acid exonuclease” activity described decades ago (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Subsequently, biochemical assays and structural studies have elaborated this function: PLD4 catalyzes the stepwise hydrolysis of phosphodiester bonds in single-stranded DNA and RNA, releasing nucleotides from the 5′ end (pmc.ncbi.nlm.nih.gov). The enzyme exhibits a preference for unphosphorylated 5′ termini – 5′-end phosphorylation on the substrate blocks activity – consistent with its need to generate a free 5′-OH before exonucleolytic digestion (pmc.ncbi.nlm.nih.gov). Indeed, purified PLD4 was shown to degrade synthetic ssDNA and ssRNA substrates processively from their 5′ ends, and to stall if a 5′ phosphate cap is present (pmc.ncbi.nlm.nih.gov). As noted, PLD4 can overcome a 5′ phosphate by acting as a 5′ phosphatase: it transiently transfers the phosphate to a catalytic histidine (forming a 3′-phosphohistidine intermediate), thereby unblocking the substrate for further digestion (pmc.ncbi.nlm.nih.gov). This dual activity was “unexpected” when first demonstrated, and highlights PLD4’s evolved role in nucleic-acid catabolism (pmc.ncbi.nlm.nih.gov).

Importantly, PLD4’s nuclease activity is optimized for the acidic pH of lysosomes (hence the term “acid exonuclease”). The enzyme shows minimal activity at neutral pH but robustly degrades nucleic acids at endosomal pH, much like DNase II (another lysosomal acid nuclease) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Together, these properties mean that PLD4 will efficiently digest nucleic acid cargo within endolysosomal compartments. It appears to prefer single-stranded nucleic acids; double-stranded DNA is likely a poor substrate unless first denatured or processed by other nucleases. Recent enzymatic analyses (2021) confirmed that PLD4 can digest single-stranded RNA as well as DNA, expanding its substrate profile to RNA degradation (pmc.ncbi.nlm.nih.gov). In mouse tissues lacking PLD3/PLD4, researchers detected an accumulation of undegraded short single-stranded RNA fragments, consistent with the loss of an RNAse activity in lysosomes (pmc.ncbi.nlm.nih.gov). There is no evidence that PLD4 can cleave phospholipids or other lipids – earlier hypotheses that it might function like PLD1/2 were dispelled by the lack of phosphatidylcholine-hydrolyzing activity (pmc.ncbi.nlm.nih.gov) and by later mutagenesis showing PLD4’s catalytic histidines are essential for nuclease, not lipase, function (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Thus, the primary biochemical function of PLD4 is as a phosphodiesterase/exonuclease acting on nucleic acid polymers.

Localization and Expression Profile

PLD4 is a membrane-bound lysosomal enzyme that carries out its function within intracellular vesicles. As a type II transmembrane protein, PLD4’s N-terminal tail (~20 amino acids) faces the cytosol, while the large C-terminal domain (with the active site) is located in the lumen of endosomes and lysosomes (pmc.ncbi.nlm.nih.gov). This topological arrangement means PLD4 encounters nucleic acids contained inside endolysosomal compartments – for example, DNA or RNA from phagocytosed microbes, apoptotic cells, or other extracellular material. Immunocytochemistry and cell fractionation studies have confirmed PLD4’s endolysosomal localization. PLD4 co-localizes with late endosome/lysosome markers (e.g. CD68, LAMP proteins) in microglia and dendritic cells (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), and electron microscopy shows PLD4 enriched on the membranes of phagosomes and multivesicular bodies (pmc.ncbi.nlm.nih.gov). In one study of cultured microglia, PLD4 redistribution was observed upon activation – resting cells showed a perinuclear pattern, whereas after stimulation, PLD4 concentrated on phagocytic vesicles containing ingested particles (pmc.ncbi.nlm.nih.gov). Consistently, knockdown of PLD4 in microglial cells impaired phagocytosis efficiency, suggesting PLD4 normally associates with the phagolysosomal pathway to help digest engulfed material (pmc.ncbi.nlm.nih.gov).

PLD4 is predominantly expressed in immune and hematopoietic tissues. It was originally noted to be highly expressed in myeloid-lineage cells – for example, in mouse microglia (brain-resident macrophages) during early postnatal development (pmc.ncbi.nlm.nih.gov), and in spleen and thymus reticuloendothelial cells (pubmed.ncbi.nlm.nih.gov). In humans, PLD4 mRNA and protein are abundant in dendritic cells (DCs), monocytes/macrophages, and certain B cell subsets (pmc.ncbi.nlm.nih.gov). By contrast, PLD4 is low or absent in most non-immune tissues, although moderate expression has been detected in the brain and other organs (likely reflecting resident immune cells in those tissues) (pubmed.ncbi.nlm.nih.gov). Notably, dendritic cells and macrophages upregulate PLD4 upon activation. For instance, human monocyte-derived DCs show increased PLD4 expression in response to Toll-like receptor agonists (pubmed.ncbi.nlm.nih.gov), and microglia strongly induce PLD4 when activated by stimuli like LPS or during demyelination injury (pmc.ncbi.nlm.nih.gov). PLD4 expression is also inducible in B cells by specific signals: stimulation of the B-cell receptor together with TLR9 ligand drives high PLD4 levels in a subset of proliferating B cells (pmc.ncbi.nlm.nih.gov). This inducible expression pattern suggests PLD4 is part of the immune system’s toolkit for handling nucleic-acid-rich material during pathogen responses or tissue cleanup.

Interestingly, recent research has shown that PLD4 can also be found outside the cell, in the form of extracellular vesicles. A 2025 study demonstrated that activated human B cells secrete PLD4-containing exosomes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In that study, PLD4 was detected in plasma extracellular vesicles (EVs) from healthy donors, and was traced to B cells as the source: upon activation, B cells reroute PLD4 from the Golgi to CD63⁺ multivesicular endosomes, which then release PLD4-positive exosomes into the extracellular space (pmc.ncbi.nlm.nih.gov). These findings reveal a novel mechanism by which PLD4 might act beyond the cell, potentially degrading nucleic acids in the extracellular environment or delivering regulatory signals to other cells (pmc.ncbi.nlm.nih.gov). The physiological role of extracellular PLD4 is still under investigation, but it could represent a way for immune cells to dispose of DNA/RNA debris outside cells or to modulate intercellular communication during immune responses (pmc.ncbi.nlm.nih.gov). In summary, PLD4’s functional arena is primarily the endolysosomal compartment of immune cells, though under certain conditions it can be released in vesicles, extending its reach to the extracellular milieu.

Biological Role and Pathways

PLD4’s enzymatic activity – degrading nucleic acids in endosomes – directly connects to its biological role in regulating innate immune signaling. Endosomal Toll-like receptors such as TLR9 (which senses CpG DNA) and TLR7/8 (which sense single-stranded RNA) rely on encountering their nucleic-acid ligands within endolysosomal compartments (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). PLD4 acts as a negative regulator of these TLR pathways by breaking down the DNA and RNA ligands, thus limiting their availability to the receptors. In the absence of PLD4, nucleic acid fragments persist longer in endosomes, leading to hyperactivation of TLR-mediated immune responses (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Experimental evidence for this role comes from gene knockout studies. Mice deficient in Pld4 develop a spontaneous inflammatory syndrome characterized by an enlarged spleen and elevated interferon-γ (IFN-γ) levels (pmc.ncbi.nlm.nih.gov). Notably, dendritic cells from Pld4⁻/⁻ mice show heightened sensitivity to TLR9 ligands – they produce excessive inflammatory cytokines when stimulated with unmethylated CpG DNA, compared to wild-type cells (pmc.ncbi.nlm.nih.gov). This indicates that normally PLD4 in those DCs helps degrade the CpG DNA after uptake, dampening the TLR9 signal. Macrophages lacking Pld4 similarly have exaggerated cytokine responses to TLR9 agonists (pmc.ncbi.nlm.nih.gov). Crucially, the Pld4⁻/⁻ inflammatory phenotype is TLR9-dependent: if TLR9 is knocked out in the Pld4⁻/⁻ background, many of the abnormal immune features (splenomegaly, IFN-γ production, etc.) are reversed (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This epistatic rescue demonstrates that PLD4’s protective role is largely to restrain TLR9-driven signaling. Mechanistically, PLD4 accelerates the turnover of TLR9’s ligand (CpG-rich DNA) in endolysosomes, preventing prolonged receptor engagement (pmc.ncbi.nlm.nih.gov). The same principle appears to apply to TLR7 and RNA ligands. Follow-up studies in 2021 showed that double-knockout mice lacking both Pld4 and Pld3 accumulate aberrant amounts of single-stranded RNA in endosomes and spontaneously develop a severe inflammatory disease (pmc.ncbi.nlm.nih.gov). These mice succumb early in life to a syndrome resembling hemophagocytic lymphohistiocytosis (HLH), marked by excessive cytokine release and immune cell hyperactivation (pmc.ncbi.nlm.nih.gov). Disabling endosomal TLR signaling (by mutating Unc93b1, a chaperone required for TLR7/9 function) completely rescued the survival and inflammation in Pld3⁻/⁻Pld4⁻/⁻ mice (pmc.ncbi.nlm.nih.gov). By contrast, removing just TLR9 or TLR7 individually provided only partial relief (pmc.ncbi.nlm.nih.gov). This indicates that both DNA-sensing and RNA-sensing pathways contribute to the pathology when PLD4/PLD3 are absent (pmc.ncbi.nlm.nih.gov). Furthermore, some residual interferon-stimulated gene expression in the double-knockout mice was eliminated only when the STING cytosolic DNA-sensing pathway was also disabled (pmc.ncbi.nlm.nih.gov). Taken together, these data establish PLD4 as a key homeostatic regulator of nucleic-acid sensing pathways: it ensures that self-DNA or RNA is efficiently cleared from endolysosomes, thereby preventing unintended activation of TLR7, TLR9, and even secondary DNA sensors like cGAS–STING (pmc.ncbi.nlm.nih.gov).

Beyond its role in controlling autoinflammatory signals, PLD4 also appears important for certain physiological processes involving phagocytosis and tissue remodeling. In the developing brain, for example, microglia transiently express high levels of PLD4 while they prune and phagocytose neural debris during postnatal myelination. Consistent with this, Pld4-knockout mice exhibit a delay in early myelination of white matter: at one week after birth, myelin basic protein levels are slightly reduced in Pld4⁻/⁻ cerebellum and corpus callosum, although they catch up to normal by day 10 (pubmed.ncbi.nlm.nih.gov). Histologically, microglia in Pld4⁻/⁻ brains showed lower CD68 expression (a lysosomal marker of activation) during this period (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov), implying that without PLD4, these cells were less activated and less efficient in clearing myelin debris. Researchers hypothesize that PLD4’s nuclease activity might facilitate the degradation of oligodendrocyte apoptotic bodies or DNA-containing debris during myelin formation, thereby promoting timely maturation of white matter (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). This is a more specialized context, but it underscores that PLD4-dependent nucleic acid clearance can impact developmental processes (in this case, indirectly affecting how quickly myelin ensheathment proceeds).

PLD4 may also have roles in the tumor microenvironment via macrophage function. A study of colon cancer found that PLD4 is predominantly expressed in M1-polarized tumor-associated macrophages, where it seems to support their anti-tumor activity (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). In human colon carcinoma samples, immunostaining showed PLD4 in macrophages of the stroma and lymph nodes, with higher expression correlating with early-stage tumors (pubmed.ncbi.nlm.nih.gov). In vitro, inhibiting PLD4 in M1-type macrophages reduced their secretion of pro-inflammatory cytokines and lessened their ability to inhibit cancer cell growth (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). These findings suggest that PLD4 contributes to the full activation of M1 macrophages. Although the mechanism wasn’t fully elucidated, one possibility is that PLD4 aids in degrading nucleic acids from tumor cells (or the tumor microenvironment), which could influence cytokine production or the presentation of tumor antigens. This area is still being explored, but it highlights how PLD4’s function in nucleic acid clearance could intersect with immune surveillance and inflammation in diseases beyond autoimmunity.

Clinical Significance and Recent Developments

Given its role in immune regulation, PLD4 has drawn attention as a gene associated with autoimmune and autoinflammatory diseases. Genome-wide association studies (GWAS) have linked polymorphisms in the human PLD4 gene to several immune-mediated conditions, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For example, a non-coding PLD4 variant (rs2841277) was identified as a risk factor in Japanese SLE patients, and PLD4 polymorphisms have also been implicated in the severity of RA (pmc.ncbi.nlm.nih.gov). These genetic links are consistent with PLD4’s function: impaired nucleic acid clearance in immune cells could predispose individuals to inappropriate activation of TLR9/TLR7, fueling autoimmune pathology. Indeed, a 2019 study showed that a loss-of-function PLD4 mutation in mice led to lupus-like phenotypes (autoantibody production, splenomegaly), reinforcing the connection between PLD4 and lupus immunopathology (pmc.ncbi.nlm.nih.gov). On the other hand, PLD4 has also been associated with neurological disorders in some studies – notably, a rare PLD4 coding mutation was linked to a form of spinocerebellar ataxia in humans (pmc.ncbi.nlm.nih.gov). It is unclear if this neurological link is due to PLD4’s intrinsic role in microglia/brain immune cells or an unrelated function, but it underscores that PLD4’s influence may extend to multiple organ systems via immune mechanisms.

From a translational perspective, PLD4 and its sister enzyme PLD3 are being examined as potential therapeutic targets or biomarkers in inflammatory diseases. Because excess type I interferon and cytokine responses drive many autoimmune conditions, enhancing the activity of PLD4 might help curtail those responses by promoting the clearance of self-DNA/RNA. Conversely, in settings like cancer or infections where a stronger immune response is desired, temporary inhibition of PLD4 could amplify nucleic-acid–mediated immune activation (e.g. boosting TLR9 agonist effects). However, any such interventions would need to balance the risk of triggering systemic inflammation (as seen in Pld4-null mice). Encouragingly, the severe inflammatory syndrome in PLD3/4 double-knockout mice provides a tractable model (spontaneous HLH) to test therapeutics: researchers noted that this Pld3⁻/⁻Pld4⁻/⁻ mouse model is unique in developing HLH spontaneously, making it useful for evaluating treatments that modulate nucleic-acid sensing without the confounding effects of infections (pmc.ncbi.nlm.nih.gov). This model is already yielding insight – for instance, it has confirmed that blocking TLR9 with specific antibodies can ameliorate the disease even after onset of symptoms (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), supporting the idea that persistent DNA sensing drives pathology in the absence of PLD3/4.

Another recent development (2024) has been the detailed mapping of disease-associated mutations in PLD4. The 3D crystal structure of PLD4, resolved in late 2023, allowed scientists to pinpoint how certain human missense variants might impact the enzyme. For example, variants linked to autoinflammatory conditions were tested and found to reduce PLD4’s exonuclease activity or stability in vitro (pubmed.ncbi.nlm.nih.gov). Some mutations destabilized the protein fold, while others occurred near the active site and likely disrupt substrate binding or catalysis (pubmed.ncbi.nlm.nih.gov). These findings provide a molecular rationale for how genetic changes in PLD4 contribute to disease – by partially impairing the enzyme’s ability to regulate nucleic acid-sensing, they may lower the threshold for inflammation. Knowing the structural impact of these mutations could guide the design of small molecules that stabilize PLD4 or enhance its activity as a therapeutic strategy.

Lastly, it’s worth noting the interdisciplinary interest in PLD4’s function. Immunologists view PLD4 as a critical “self-tolerance” factor that prevents spontaneous interferon release (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Neurologists are examining PLD4 in the context of microglial biology and myelination (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Cancer researchers are investigating how PLD4 in macrophages influences tumor immunity (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). This convergence of research reflects the gene’s broad impact on physiological processes that involve clearing nucleic acids. In summary, human PLD4 is now understood to be a lysosomal 5′-exonuclease with a specialized role in “garbage disposal” of DNA/RNA inside immune cells. By doing so, it protects the body from unwarranted immune activation. Ongoing studies (many from 2023–2024) are refining our understanding of its mechanism – for instance, how exactly it partners with other nucleases or sensors – and exploring ways to modulate PLD4’s activity in diseases. With its unique position at the crossroads of metabolism and immunity, PLD4 exemplifies how fine-tuned control of molecular waste products (like nucleic acid debris) is crucial for preventing inflammation and maintaining homeostasis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Citations

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  25. AnnotationURLCitation(end_index=7345, start_index=7229, title='Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10690185/#:~:text=%E2%80%98link,Biochemical%20and')
  26. AnnotationURLCitation(end_index=7806, start_index=7626, 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=Evidence%20is%20mounting%20that%20regulation,differing%20tissues%20and%20cellular%20compartments')
  27. AnnotationURLCitation(end_index=7977, start_index=7807, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Nucleic%20acid%20sensing%20is%20important,unmethylated%20CpG%20motifs%2C%20and%20TLR13')
  28. AnnotationURLCitation(end_index=8569, start_index=8409, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=important%20inflammatory%20diseases,by%20inflammatory%20liver%20damage%20and')
  29. AnnotationURLCitation(end_index=8914, start_index=8754, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=important%20inflammatory%20diseases,by%20inflammatory%20liver%20damage%20and')
  30. AnnotationURLCitation(end_index=9243, start_index=9115, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=Phospholipase%20D4%20,A%20primary%20cultured')
  31. AnnotationURLCitation(end_index=9460, start_index=9354, title='Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38537643/#:~:text=interface,Biochemical%20and')
  32. AnnotationURLCitation(end_index=9639, start_index=9461, title='Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38537643/#:~:text=captured%20structures%20in%20apo%2C%20intermediate%2C,stabilizes%20substrate%20and%20could%20affect')
  33. AnnotationURLCitation(end_index=10221, start_index=10116, 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=,25%2C%2024%7D.%20The')
  34. AnnotationURLCitation(end_index=10801, start_index=10657, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=Phospholipase%20D4%20,significant%20delay%20in%20myelination%20in')
  35. AnnotationURLCitation(end_index=10976, start_index=10802, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=microglia%20and%20microglial%20cell%20line,pathological%20conditions%20of%20white%20matter')
  36. AnnotationURLCitation(end_index=11253, start_index=11079, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=microglia%20and%20microglial%20cell%20line,pathological%20conditions%20of%20white%20matter')
  37. AnnotationURLCitation(end_index=11658, start_index=11484, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=microglia%20and%20microglial%20cell%20line,pathological%20conditions%20of%20white%20matter')
  38. AnnotationURLCitation(end_index=12025, start_index=11851, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=microglia%20and%20microglial%20cell%20line,pathological%20conditions%20of%20white%20matter')
  39. AnnotationURLCitation(end_index=12407, start_index=12279, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=Phospholipase%20D4%20,A%20primary%20cultured')
  40. AnnotationURLCitation(end_index=12548, start_index=12460, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=%28PLD4,5')
  41. AnnotationURLCitation(end_index=12846, start_index=12676, 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=functions%20of%20PLD3%20and%20PLD4,are%205%E2%80%B2%20exonucleases%20with%20properties')
  42. AnnotationURLCitation(end_index=13135, start_index=13047, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=%28PLD4,5')
  43. AnnotationURLCitation(end_index=13451, start_index=13330, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40811510/#:~:text=enzyme,These%20findings%20establish%20that')
  44. AnnotationURLCitation(end_index=13736, start_index=13554, title='PLD4 Is Involved in Phagocytosis of Microglia: Expression and Localization Changes of PLD4 Are Correlated with Activation State of Microglia - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3216956/#:~:text=Immunohistochemical%20analysis%20revealed%20that%20PLD4,significantly%20reduced%20the%20ratio%20of')
  45. AnnotationURLCitation(end_index=14106, start_index=13930, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=contain%20PLD4%20through%20immunoelectron%20microscopy,that%20PLD4%20relocates%20from%20the')
  46. AnnotationURLCitation(end_index=14651, start_index=14503, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=Phospholipase%20D4%20,cell%20receptor%20engagement%20and%20TLR9')
  47. AnnotationURLCitation(end_index=14792, start_index=14652, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=agonist,role%20in%20intercellular%20communication%20and')
  48. AnnotationURLCitation(end_index=15227, start_index=15087, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=agonist,role%20in%20intercellular%20communication%20and')
  49. AnnotationURLCitation(end_index=15571, start_index=15431, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=agonist,role%20in%20intercellular%20communication%20and')
  50. AnnotationURLCitation(end_index=15944, start_index=15804, title='Activated human B cells produce phospholipase D4-containing extracellular vesicles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12352752/#:~:text=agonist,role%20in%20intercellular%20communication%20and')
  51. AnnotationURLCitation(end_index=16708, start_index=16542, 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=type%20I%20interferons%20%28IFN%29%2C%20IFN,RLRs%29%20recognize%20uncapped%20dsRNA')
  52. AnnotationURLCitation(end_index=16842, start_index=16709, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=pathways%20involving%20MAVS%2C%20STING%2C%20or,11')
  53. AnnotationURLCitation(end_index=17240, start_index=17133, 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=PLD4,Macrophages%20from')
  54. AnnotationURLCitation(end_index=17412, start_index=17241, 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=an%20altered%20responsiveness%20of%20PLD4,that%20they%20are%205%E2%80%B2%20exonucleases')
  55. AnnotationURLCitation(end_index=17740, start_index=17633, 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=PLD4,Macrophages%20from')
  56. AnnotationURLCitation(end_index=18059, start_index=17952, 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=PLD4,Macrophages%20from')
  57. AnnotationURLCitation(end_index=18434, start_index=18263, 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=an%20altered%20responsiveness%20of%20PLD4,that%20they%20are%205%E2%80%B2%20exonucleases')
  58. AnnotationURLCitation(end_index=18809, start_index=18644, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=overproduction%20of%20Interferon%20%28IFN%29,for%20the%20treatment%20of%20nucleic')
  59. AnnotationURLCitation(end_index=18923, start_index=18810, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Unc93b1,3d%2F3d%7D%20mutation')
  60. AnnotationURLCitation(end_index=19342, start_index=19176, 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=acid%20exonuclease%20or%20phosphodiesterase,turnover%20of%2C%20ligands%20of%20TLR9')
  61. AnnotationURLCitation(end_index=19771, start_index=19611, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=important%20inflammatory%20diseases,by%20inflammatory%20liver%20damage%20and')
  62. AnnotationURLCitation(end_index=20102, start_index=19942, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=important%20inflammatory%20diseases,by%20inflammatory%20liver%20damage%20and')
  63. AnnotationURLCitation(end_index=20407, start_index=20274, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Unc93b1,a%20minor%20contribution%20to%20pathology')
  64. AnnotationURLCitation(end_index=20624, start_index=20491, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Unc93b1,a%20minor%20contribution%20to%20pathology')
  65. AnnotationURLCitation(end_index=20879, start_index=20746, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Unc93b1,a%20minor%20contribution%20to%20pathology')
  66. AnnotationURLCitation(end_index=21203, start_index=21061, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=match%20at%20L35%20Unc93b1,driven%20inflammatory%20disease')
  67. AnnotationURLCitation(end_index=21636, start_index=21494, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=match%20at%20L35%20Unc93b1,driven%20inflammatory%20disease')
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  69. AnnotationURLCitation(end_index=22647, start_index=22503, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=Phospholipase%20D4%20,significant%20delay%20in%20myelination%20in')
  70. AnnotationURLCitation(end_index=22798, start_index=22648, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=PLD4%20expression%20is%20highest%20in,role%20in%20myelination%20via%20a')
  71. AnnotationURLCitation(end_index=23275, start_index=23131, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=Phospholipase%20D4%20,significant%20delay%20in%20myelination%20in')
  72. AnnotationURLCitation(end_index=23416, start_index=23276, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=protein%20,primarily%20influences%20the%20early%20myelination')
  73. AnnotationURLCitation(end_index=24013, start_index=23884, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=However%2C%20the%20function%20of%20PLD4,siRNA%20M1')
  74. AnnotationURLCitation(end_index=24162, start_index=24014, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=Western%20blot%20and%20RT,process%20of%20M1%20phenotype%20macrophages')
  75. AnnotationURLCitation(end_index=24459, start_index=24330, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=However%2C%20the%20function%20of%20PLD4,siRNA%20M1')
  76. AnnotationURLCitation(end_index=24784, start_index=24621, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=clinical%20staging%20of%20colon%20cancer,process%20of%20M1%20phenotype%20macrophages')
  77. AnnotationURLCitation(end_index=24924, start_index=24785, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=phenotype%20TAMs,process%20of%20M1%20phenotype%20macrophages')
  78. AnnotationURLCitation(end_index=26009, start_index=25859, 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=compartments%20distinct%20from%20most%20other,25%2C%2024%7D.%20The')
  79. AnnotationURLCitation(end_index=26181, start_index=26010, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=systemic%20sclerosis%2C%20systemic%20lupus%20erythematosus,22%E2%80%9325%7D.%20Although')
  80. AnnotationURLCitation(end_index=26538, start_index=26367, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=systemic%20sclerosis%2C%20systemic%20lupus%20erythematosus,22%E2%80%9325%7D.%20Although')
  81. AnnotationURLCitation(end_index=27099, start_index=26958, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=,214116.%20%5BDOI%5D%20%5BPubMed%5D%20%5BGoogle%20Scholar')
  82. AnnotationURLCitation(end_index=27449, start_index=27296, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=PLD3%20and%20PLD4%20are%20phospholipase,31%2C29%7D.%20We%20previously')
  83. AnnotationURLCitation(end_index=28908, start_index=28761, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=by%20multiple%20sensors%20,the%20latter%20models%20may%20affect')
  84. AnnotationURLCitation(end_index=29247, start_index=29082, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=overproduction%20of%20Interferon%20%28IFN%29,for%20the%20treatment%20of%20nucleic')
  85. AnnotationURLCitation(end_index=29381, start_index=29248, title='Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8497607/#:~:text=Unc93b1,a%20minor%20contribution%20to%20pathology')
  86. AnnotationURLCitation(end_index=30061, start_index=29879, title='Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38537643/#:~:text=captured%20structures%20in%20apo%2C%20intermediate%2C,findings%20provide%20insight%20into%20therapeutic')
  87. AnnotationURLCitation(end_index=30384, start_index=30202, title='Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38537643/#:~:text=captured%20structures%20in%20apo%2C%20intermediate%2C,findings%20provide%20insight%20into%20therapeutic')
  88. AnnotationURLCitation(end_index=31103, start_index=30965, 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=sclerosis,lethal%20early%20life%20liver%20inflammation')
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  91. AnnotationURLCitation(end_index=31645, start_index=31505, title='Microglial phospholipase D4 deficiency influences myelination during brain development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27477458/#:~:text=protein%20,primarily%20influences%20the%20early%20myelination')
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  93. AnnotationURLCitation(end_index=32027, start_index=31864, title='PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27840999/#:~:text=clinical%20staging%20of%20colon%20cancer,process%20of%20M1%20phenotype%20macrophages')
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