PLD4 is a multifunctional transmembrane enzyme that, despite its misleading name, lacks phospholipase D activity and instead functions as a 5'-3' exonuclease and transphosphatidylase. The protein degrades single-stranded DNA and RNA in endolysosomes to prevent inappropriate activation of TLR9 by self-derived mitochondrial DNA while enabling TLR7 activation by processing viral RNA. Additionally, PLD4 synthesizes bis(monoacylglycero)phosphate (BMP), a critical lipid component of lysosomal intralumenal vesicles essential for lipid degradation and autophagy. Predominantly localized to the ER membrane with dynamic trafficking to Golgi and endolysosomes, PLD4 plays crucial roles in immune regulation, preventing autoimmune responses, and maintaining endolysosomal homeostasis. In microglia, it participates in phagocytosis with characteristic redistribution from nucleus to phagosomes upon activation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | ACCEPT | Summary: PLD4 is indeed localized to the endomembrane system, particularly the ER membrane and Golgi apparatus as confirmed by multiple studies (PMID:21085684, PMID:22102906). The IBA annotation correctly captures this broad cellular localization. Reason: The endomembrane system annotation is well-supported by experimental evidence showing PLD4 localization to ER membrane, Golgi apparatus, and endolysosomes. This IBA annotation represents an appropriate level of specificity. Supporting Evidence: PMID:21085684 EGFP fluorescence formed a meshwork-like structure in the peripheral region of the nucleus in HEK293 cells... PLD4 immunoreactivity was co-localized with calnexin, an endoplasmic reticulum (ER) resident protein... and PLD4 expression also formed a clustered pattern with golgin 97, a trans-Golgi network protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0006909 phagocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PLD4 participates in microglial phagocytosis and redistributes to phagosomes during activation, but phagocytosis is a cell-context phenotype rather than the main biochemical function of PLD4. Reason: Falcon synthesis identifies PLD4 core activities as acidic endolysosomal 5-prime-to-3-prime exonuclease activity and S,S-BMP synthase/transphosphatidylase activity. Phagocytosis is retained as a supported non-core immune-cell process. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0002376 immune system process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: PLD4 contributes to immune system processes through endolysosomal nucleic-acid and lipid metabolism, but this term is very broad. Reason: More specific annotations capture the core biology: endolysosomal exonuclease activity, regulation of TLR9/TLR7 nucleic-acid sensing, and BMP synthesis. Retain this as a non-core umbrella process. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: PLD4 is catalytic, but the parent term catalytic activity is too general for curation. Direct evidence supports acidic 5-prime-to-3-prime exonuclease activity on ssDNA/ssRNA and S,S-BMP synthase/transphosphatidylase activity. Reason: Replace the generic parent with the specific activities supported by Falcon synthesis and primary biochemical work. Proposed replacements: single-stranded DNA 5'-3' DNA exonuclease activity bis(monoacylglycero)phosphate synthase activity Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0004518 nuclease activity | IEA GO_REF:0000043 | ACCEPT | Summary: PLD4 does have nuclease activity, specifically functioning as a 5'-3' exonuclease on single-stranded DNA and RNA. This annotation is correct but could be more specific. Reason: The nuclease activity annotation is correct. PLD4 functions as a 5'-3' exonuclease that degrades ssDNA and RNA. While more specific terms exist (GO:0004527 for exonuclease activity), this parent term is acceptable for an IEA annotation. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md 5'->3' exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3'- monophosphates and 5'-end 5'-hydroxy deoxyribonucleotide/ribonucleotide fragments file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0004527 exonuclease activity | IEA GO_REF:0000043 | ACCEPT | Summary: PLD4 has 5'-3' exonuclease activity on single-stranded DNA and RNA. This annotation is correct and represents a core molecular function. Reason: The exonuclease activity annotation is accurate. PLD4 functions as a 5'-3' exonuclease that degrades ssDNA and RNA to produce nucleoside 3'-monophosphates. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md 5'->3' exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3'- monophosphates file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: PLD4 shows some nuclear localization in microglia, particularly in resting state, but this is not its primary localization. It redistributes from nucleus to phagosomes upon activation. Reason: While PLD4 can be found in the nucleus of resting microglia, this is a transient localization that changes with cell activation state. The primary localizations are ER membrane and endolysosomes. Supporting Evidence: PMID:22102906 Primary cultured microglia and the microglial cell line MG6 showed that PLD4 immuno-signals were mainly present in the nucleus, apart from the nucleolus file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: PLD4 localizes to lysosomes where it performs critical functions including nucleic acid degradation and BMP synthesis. This is a core localization. Reason: Lysosomal localization is well-supported. PLD4 synthesizes BMP, the main phospholipid constituent of lysosomal intralumenal vesicle membranes, and degrades nucleic acids in the endolysosomal compartment. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md Can synthesize a variety of (S,S)-BMPs representing the main phospholipid constituent of lysosomal intralumenal vesicle (ILV) membranes that bind acid hydrolases for lipid degradation file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005768 endosome | IEA GO_REF:0000117 | ACCEPT | Summary: PLD4 localizes to endosomes as part of the endolysosomal pathway where it processes nucleic acids for immune sensing. This is a core localization. Reason: Endosomal localization is well-supported. PLD4 processes nucleic acids that reach the endolysosomal compartment and participates in immune surveillance. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md Processes self and pathogenic ssDNA and RNA molecules that reach the endolysosomal compartment via phagocytosis or autophagy file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005769 early endosome | IEA GO_REF:0000044 | MODIFY | Summary: PLD4 localizes to transferrin-positive BioParticle-containing early phagosomes during microglial phagocytosis, not generic early endosomes. Reason: PMID:22102906 describes PLD4 in BioParticle-containing early phagosomes. Replace the generic early endosome component with the more precise early phagosome term. Proposed replacements: early phagosome Supporting Evidence: PMID:22102906 The results suggest that PLD4 is predominantly present in early phagosomes file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: PLD4 is predominantly localized to the ER membrane as confirmed by multiple studies. This is its primary subcellular localization and represents a core component. Reason: ER membrane localization is well-established by experimental evidence. PLD4 is a transmembrane glycoprotein that resides primarily in the ER membrane. Supporting Evidence: PMID:21085684 PLD4 immunoreactivity was co-localized with calnexin, an endoplasmic reticulum (ER) resident protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: PLD4 localizes to the Golgi apparatus, particularly the trans-Golgi network, as shown by colocalization studies. Reason: Golgi localization is supported by experimental evidence showing PLD4 colocalization with trans-Golgi network markers. Supporting Evidence: PMID:21085684 PLD4 expression also formed a clustered pattern with golgin 97, a trans-Golgi network protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0006259 DNA metabolic process | IEA GO_REF:0000108 | ACCEPT | Summary: DNA metabolism via PLD4 exonuclease activity on ssDNA. Reason: PLD4 degrades ssDNA in endolysosomes, contributing to nucleic acid metabolism. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md 5'->3' exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3'- monophosphates file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: PLD4 synthesizes BMP lipids in lysosomes. Reason: PLD4 catalyzes BMP synthesis, a lipid metabolic process in endolysosomes. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md Can synthesize a variety of (S,S)-BMPs representing the main phospholipid constituent of lysosomal intralumenal vesicle (ILV) membranes file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0006954 inflammatory response | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: PLD4 is linked to microglial activation and inflammatory contexts. Reason: Inflammatory responses are context-dependent downstream outcomes of microglial activation. Supporting Evidence: PMID:22102906 Binding of antibodies to Fc receptors on the microglial surface induces phagocytosis activity in microglia, which is associated with inflammation file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Broad hydrolase annotation for PLD4 exonuclease activity. Reason: PLD4 functions as a hydrolase through its exonuclease activity. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md 5'->3' exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: PLD4 associates with phagocytic vesicles in microglia. Reason: Vesicular localization is context-dependent in activated microglia. Supporting Evidence: PMID:22102906 PLD4 immunoreactivity accumulated in phagosomes when BioParticles were added to primary microglial cultures file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: PLD4 processes nucleic acids that act as innate immune danger signals. Reason: PLD4 modulates innate immune receptor activation through nucleic acid processing. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md Processes self and pathogenic ssDNA and RNA molecules that reach the endolysosomal compartment via phagocytosis or autophagy and may serve as danger signals for recognition by innate immune receptors such as toll-like receptors (TLRs) file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0045145 single-stranded DNA 5'-3' DNA exonuclease activity | IEA GO_REF:0000117 | ACCEPT | Summary: PLD4 has 5'-3' exonuclease activity on single-stranded DNA. This is one of its core molecular functions, degrading ssDNA to produce nucleoside 3'-monophosphates. Reason: This annotation correctly identifies PLD4's core exonuclease function. The protein degrades single-stranded DNA in a 5' to 3' direction, which is critical for preventing inappropriate TLR9 activation. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md 5'->3' exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3'- monophosphates file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: PLD4 localizes to phagocytic vesicles in microglia. Reason: PLD4 accumulates in phagosomes during phagocytosis. Supporting Evidence: PMID:22102906 PLD4 immunoreactivity accumulated in phagosomes when BioParticles were added to primary microglial cultures file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:1900015 regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: PLD4 loss or combined PLD3/PLD4 loss can alter cytokine and inflammatory outputs by changing endosomal nucleic-acid sensing, but cytokine regulation is downstream of the enzymatic function. Reason: Falcon synthesis supports cytokine dysregulation as an immune consequence of defective endolysosomal nucleic-acid clearance. Retain as supported non-core biology rather than a core function. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0004630 D-type glycerophospholipase activity | TAS Reactome:R-MMU-1483172 | REMOVE | Summary: This is a positive Reactome annotation to phospholipase D activity, but experimental evidence shows PLD4 lacks authentic PLD activity. Reason: The GOA has a separate explicit NOT annotation for this term. The positive Reactome TAS row should be removed because PMID:21085684 directly refutes authentic phospholipase D activity for PLD4. Supporting Evidence: PMID:21085684 these results suggested that PLD4 is a HKD motif-containing protein family member that lacks authentic PLD activity file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0004630 D-type glycerophospholipase activity | IDA NOT PMID:21085684 Phospholipase D family member 4, a transmembrane glycoprotei... | ACCEPT | Summary: This annotation has a NOT qualifier in the GOA file (line 24), indicating PLD4 does NOT have phospholipase D activity. This negative annotation correctly reflects that PLD4 lacks this activity despite its misleading name. Reason: This is a negative annotation (NOT enables GO:0004630) that correctly documents the experimental finding that PLD4 lacks phospholipase D activity. The study explicitly tested and disproved PLD activity. Supporting Evidence: PMID:21085684 However, cell lysates transfected with PLD4 did not exhibit significant PLD activity, such as cells transfected with vector alone file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005634 nucleus | IDA PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | KEEP AS NON CORE | Summary: PLD4 is nuclear in resting microglia. Reason: Nuclear localization is context-dependent and not the primary localization. Supporting Evidence: PMID:22102906 PLD4 immuno-signals were mainly present in the nucleus, apart from the nucleolus file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005769 early endosome | IDA PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | MODIFY | Summary: PLD4 accumulates in early phagosomes during microglial activation. Reason: The PMID:22102906 microscopy supports early phagosome localization. The existing early endosome term is less accurate because the transferrin-positive structures are BioParticle-containing phagosomes. Proposed replacements: early phagosome Supporting Evidence: PMID:22102906 In the phagocytotic state eating BioParticles, PLD4 accumulated in the early phagosomes. file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0045145 single-stranded DNA 5'-3' DNA exonuclease activity | IMP PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | REMOVE | Summary: The 2011 microglial paper does not itself biochemically demonstrate exonuclease activity, but the annotation is now directly supported by later biochemical and structural work showing PLD4 is a single-stranded DNA 5-prime-to-3-prime exonuclease. Reason: The term is correct for PLD4, but this specific PMID:22102906 IMP annotation is unsupported because that paper localized PLD4 in activated microglia and did not demonstrate exonuclease activity. The function is retained through the other ssDNA exonuclease annotation supported by PMID:30111894. Supporting Evidence: PMID:30111894 PLD4 degraded a 55 nt ssDNA |
| GO:0045335 phagocytic vesicle | IDA PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | ACCEPT | Summary: PLD4 accumulates in phagosomes during phagocytosis. Reason: Direct microscopy shows PLD4 in phagosomes during microglial activation. Supporting Evidence: PMID:22102906 PLD4 immunoreactivity accumulated in phagosomes when BioParticles were added to primary microglial cultures file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:1900015 regulation of cytokine production involved in inflammatory response | IMP PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | KEEP AS NON CORE | Summary: PLD4 loss or combined PLD3/PLD4 loss can alter cytokine and inflammatory outputs by changing endosomal nucleic-acid sensing, but cytokine regulation is downstream of the enzymatic function. Reason: Falcon synthesis supports cytokine dysregulation as an immune consequence of defective endolysosomal nucleic-acid clearance. Retain as supported non-core biology rather than a core function. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:21085684 Phospholipase D family member 4, a transmembrane glycoprotei... | ACCEPT | Summary: PLD4 localizes to the ER membrane. Reason: Colocalization with ER markers supports ER membrane localization. Supporting Evidence: PMID:21085684 PLD4 immunoreactivity was co-localized with calnexin, an endoplasmic reticulum (ER) resident protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0032588 trans-Golgi network membrane | IDA PMID:21085684 Phospholipase D family member 4, a transmembrane glycoprotei... | ACCEPT | Summary: PLD4 localizes to the trans-Golgi network. Reason: Colocalization with golgin 97 supports trans-Golgi network localization. Supporting Evidence: PMID:21085684 PLD4 expression also formed a clustered pattern with golgin 97, a trans-Golgi network protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0002244 hematopoietic progenitor cell differentiation | IMP PMID:24029230 Haploinsufficiency of SAMD9L, an endosome fusion facilitator... | UNDECIDED | Summary: Cannot be adjudicated here: PMID:24029230 is cached abstract-only. Prior observation, not a verdict: The cited publication is about Samd9l haploinsufficiency and myeloid malignancy, not a direct functional role of Pld4 in hematopoietic progenitor differentiation. Reason: PMID:24029230 is cached abstract-only, so the curator's experimental evidence cannot be inspected here; per CLAUDE.md an experimental annotation is not overruled on that basis. Recorded observation, not a verdict: No reviewed Pld4 literature or Falcon synthesis supports hematopoietic progenitor differentiation as a Pld4 function. This appears to be an erroneous or indirect annotation and was questioned. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005783 endoplasmic reticulum | IDA PMID:21085684 Phospholipase D family member 4, a transmembrane glycoprotei... | ACCEPT | Summary: PLD4 localizes to the ER. Reason: ER localization is supported by colocalization with ER markers. Supporting Evidence: PMID:21085684 PLD4 immunoreactivity was co-localized with calnexin, an endoplasmic reticulum (ER) resident protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0006909 phagocytosis | IMP PMID:22102906 PLD$ is involved in phagocytosis of microglia: expression an... | KEEP AS NON CORE | Summary: PLD4 participates in microglial phagocytosis and redistributes to phagosomes during activation, but phagocytosis is a cell-context phenotype rather than the main biochemical function of PLD4. Reason: Falcon synthesis identifies PLD4 core activities as acidic endolysosomal 5-prime-to-3-prime exonuclease activity and S,S-BMP synthase/transphosphatidylase activity. Phagocytosis is retained as a supported non-core immune-cell process. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-MMU-1483172 | ACCEPT | Summary: ER membrane localization in agreement with experimental evidence. Reason: PLD4 localizes to the ER membrane based on colocalization studies. Supporting Evidence: PMID:21085684 PLD4 immunoreactivity was co-localized with calnexin, an endoplasmic reticulum (ER) resident protein file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0005515 protein binding | IPI PMID:18706977 Interaction assays in yeast and cultured cells confirm known... | REMOVE | Summary: Generic protein binding annotation is uninformative. Reason: Protein binding is too general to be useful for PLD4 function. Supporting Evidence: PMID:18706977 Interaction assays in yeast and cultured cells confirm known and identify novel partners of the synaptic vesicle protein synaptophysin. file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0036019 endolysosome | NAS | NEW | Summary: PLD4 carries out its nuclease and BMP-synthase functions in endolysosomal/lysosomal compartments. Reason: Endolysosomal localization is directly tied to acidic-pH catalytic activity and nucleic-acid/lipid substrate availability. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0034164 negative regulation of toll-like receptor 9 signaling pathway | NAS | NEW | Summary: PLD4 degrades endolysosomal self ssDNA, including mitochondrial CpG-rich DNA, thereby limiting inappropriate TLR9 activation. Reason: This is a direct biological consequence of the core exonuclease function and is well supported by Falcon synthesis and primary PLD3/PLD4 studies. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0160121 bis(monoacylglycero)phosphate synthase activity | NAS | NEW | Summary: Falcon synthesis and the 2024 Cell study support PLD4 as an S,S-BMP synthase/transphosphatidylase in lysosomes. Reason: This specific molecular function is directly supported by purified enzyme and tissue lipidomic evidence and is not represented by the older broad catalytic-activity annotation. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:2001312 lysobisphosphatidic acid biosynthetic process | NAS | NEW | Summary: PLD4-dependent S,S-BMP synthesis supports lysobisphosphatidic acid/BMP biosynthesis in lysosomes. Reason: The 2024 Falcon report and Cell study support this NEW process term as a direct consequence of PLD4 BMP synthase activity. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0004534 5'-3' RNA exonuclease activity | NAS | NEW | Summary: PLD4 has single-stranded RNA exonuclease activity and can shape endosomal TLR7-dependent antiviral sensing outputs. Reason: Direct PLD3/PLD4 nuclease studies support RNA cleavage and altered nucleic-acid sensor activation. Retain as conservative NEW support for the RNA/TLR7 arm of PLD4 biology. Supporting Evidence: file:mouse/Pld4/Pld4-deep-research-falcon.md [Falcon deep-research synthesis used for this annotation decision.] |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | NAS | NEW | Summary: PLD4/PLD3 ssRNA degradation limits inappropriate endosomal nucleic-acid-sensor activation and resulting autoinflammation. Reason: The accessible RNA nuclease evidence supports negative regulation of TLR/nucleic-acid sensor activation from accumulated self ssRNA, not direct positive TLR7 signaling or antiviral defense. Supporting Evidence: PMID:34620855 Pld3-/-Pld4-/- mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis |
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