AGO4 encodes human Argonaute-4, a small-RNA-binding Argonaute paralog that contributes to RISC-mediated gene regulation primarily through non-slicing mechanisms. Evidence supports miRNA/RISC-associated translational repression, cytoplasmic miRISC/P-body-associated function, and a non-core mammalian antiviral role rather than canonical AGO2-like slicing. Its lack of slicer activity does not prevent precursor-derived duplex unwinding during RISC maturation or recruitment of TNRC6-dependent mRNA decay.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: nucleus is a plausible or reported location/context but is not the core functional site annotation for AGO4. Reason: The core location is cytoplasmic RISC/RNP granules; nuclear, membrane, synaptic, exosomal, or other compartment annotations should remain non-core unless tied to a specific curated mechanism. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0004521 RNA endonuclease activity | IBA GO_REF:0000033 | REMOVE | Summary: RNA endonuclease activity is not supported as a physiological activity for AGO4. Reason: AGO4-specific loss of the conserved catalytic Asp/His, corroborated by human Argonaute cleavage experiments, contradicts retention of ancestral slicer activity. The existing OpenScientist report identifies AGO4 Gly671 and Arg809 in aligned catalytic windows. This is a target-specific challenge to the inherited catalytic assertion; the PAINT node placement was not independently reconstructed. Non-slicing RNA binding, RISC maturation and decay recruitment remain supported. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN008584027 SUPPORTS SOURCE BUT NOT TARGET Proximate IBA ancestral node verified in the cached GOA WITH/FROM field. Target-specific loss of the catalytic apparatus, documented in the cited primary/sequence evidence, challenges retention of this ancestral reaction. The full PAINT reconstruction was not independently repeated; extant donor count or target self-inclusion is not evidence against the annotation. Supporting Evidence: file:human/AGO4/AGO4-goa.tsv UniProtKB Q9HCK5 AGO4 enables GO:0004521 RNA endonuclease activity molecular_function ECO:0000318 IBA GO_REF:0000033 FB:FBgn0000146|FB:FBgn0004872|FB:FBgn0087035|FB:FBgn0250816|FB:FBgn0262739|MGI:MGI:1928897|MGI:MGI:1930036|MGI:MGI:2446632|PANTHER:PTN008584027|PomBase:SPCC736.11|TAIR:locus:2007760|TAIR:locus:2059258|UniProtKB:O67434|UniProtKB:Q9H9G7|UniProtKB:Q9UKV8|WB:WBGene00000105|WB:WBGene00000106|WB:WBGene00004323|WB:WBGene00017641 9606 Homo sapiens GO_Central Protein argonaute-4 20241120 file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** file:human/AGO4/AGO4-hypotheses/function-hypothesis-go-0004521/openscientist.md Human AGO4 does **not** have RNA endonuclease (slicer) activity. file:human/AGO4/AGO4-hypotheses/function-hypothesis-go-0004521/openscientist.md the catalytic aspartate (D669) aligns to a **glycine** in AGO4. file:human/AGO4/AGO4-hypotheses/function-hypothesis-go-0004521/openscientist.md the catalytic histidine (H807) aligns to an **arginine** in AGO4. |
| GO:0035194 regulatory ncRNA-mediated post-transcriptional gene silencing | IBA GO_REF:0000033 | ACCEPT | Summary: regulatory ncRNA-mediated post-transcriptional gene silencing is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0016442 RISC complex | IBA GO_REF:0000033 | ACCEPT | Summary: RISC complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0036464 cytoplasmic ribonucleoprotein granule | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasmic ribonucleoprotein granule is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0031054 pre-miRNA processing | IBA GO_REF:0000033 | ACCEPT | Summary: AGO4 participates in miRNA maturation by binding precursor-derived duplexes and promoting passenger-strand unwinding/ejection during RISC activation. Reason: QuickGO defines miRNA processing as generation of a functional miRNA and pre-miRNA processing as conversion to a mature miRNA molecule; neither is restricted to endonucleolytic cleavage. PMID:19966796 and PMID:22795694 demonstrate loading and slicing-independent maturation by Ago1/3/4. AGO4 supplies RNA binding and structural activity that performs part of this process, rather than merely being its substrate. This does not assign Drosha/Dicer catalysis to AGO4. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000527278 SUPPORTS TRANSFER Proximate IBA node verified in the cached GOA WITH/FROM field. Direct AGO4 RNA-binding and slicing-independent RISC-maturation experiments support this inherited noncatalytic function; the former granularity/role objection was too strong. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0035198 miRNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: miRNA binding is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0003727 single-stranded RNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000527276 SUPPORTS TRANSFER Proximate IBA node verified in the cached GOA WITH/FROM field. Direct AGO4 RNA-binding and slicing-independent RISC-maturation experiments support this inherited noncatalytic function; the former granularity/role objection was too strong. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0000932 P-body | IEA GO_REF:0000120 | ACCEPT | Summary: P-body is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0003723 RNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0003725 double-stranded RNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0003727 single-stranded RNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0016442 RISC complex | IEA GO_REF:0000120 | ACCEPT | Summary: RISC complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0031054 pre-miRNA processing | IEA GO_REF:0000117 | ACCEPT | Summary: AGO4 participates in miRNA maturation by binding precursor-derived duplexes and promoting passenger-strand unwinding/ejection during RISC activation. Reason: QuickGO defines miRNA processing as generation of a functional miRNA and pre-miRNA processing as conversion to a mature miRNA molecule; neither is restricted to endonucleolytic cleavage. PMID:19966796 and PMID:22795694 demonstrate loading and slicing-independent maturation by Ago1/3/4. AGO4 supplies RNA binding and structural activity that performs part of this process, rather than merely being its substrate. This does not assign Drosha/Dicer catalysis to AGO4. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0035198 miRNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: miRNA binding is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0035278 miRNA-mediated gene silencing by inhibition of translation | IEA GO_REF:0000120 | ACCEPT | Summary: miRNA-mediated gene silencing by inhibition of translation is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0036464 cytoplasmic ribonucleoprotein granule | IEA GO_REF:0000117 | ACCEPT | Summary: cytoplasmic ribonucleoprotein granule is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0070578 RISC-loading complex | IEA GO_REF:0000117 | ACCEPT | Summary: RISC-loading complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0070922 RISC complex assembly | IEA GO_REF:0000117 | ACCEPT | Summary: RISC complex assembly is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005515 protein binding | IPI PMID:19167051 Importin 8 is a gene silencing factor that targets argonaute... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:19167051 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005515 protein binding | IPI PMID:19324964 The C-terminal half of human Ago2 binds to multiple GW-rich ... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:19324964 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005515 protein binding | IPI PMID:19383768 The C-terminal domains of human TNRC6A, TNRC6B, and TNRC6C s... | MODIFY | Summary: AGO4 connects a guide/target RNA complex to TNRC6 silencing factors. Reason: The paper demonstrates interaction of all four AGOs with TNRC6 N-terminal regions and assigns TNRC6 recruitment to Argonaute. Combined with AGO4 RNA-binding evidence, this supports molecular adaptor activity rather than generic protein binding. Proposed replacements: molecular adaptor activity Supporting Evidence: PMID:19383768 the N-terminal GW-repeat-containing regions of all three TNRC6s interact with the four human Argonaute proteins (AGO1-AGO4). PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:33961781 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: nucleus is a plausible or reported location/context but is not the core functional site annotation for AGO4. Reason: The core location is cytoplasmic RISC/RNP granules; nuclear, membrane, synaptic, exosomal, or other compartment annotations should remain non-core unless tied to a specific curated mechanism. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0035196 miRNA processing | NAS PMID:28781232 Multivalent Recruitment of Human Argonaute by GW182. | ACCEPT | Summary: AGO4 participates in miRNA maturation by binding precursor-derived duplexes and promoting passenger-strand unwinding/ejection during RISC activation. Reason: QuickGO defines miRNA processing as generation of a functional miRNA and pre-miRNA processing as conversion to a mature miRNA molecule; neither is restricted to endonucleolytic cleavage. PMID:19966796 and PMID:22795694 demonstrate loading and slicing-independent maturation by Ago1/3/4. AGO4 supplies RNA binding and structural activity that performs part of this process, rather than merely being its substrate. This does not assign Drosha/Dicer catalysis to AGO4. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0036464 cytoplasmic ribonucleoprotein granule | IDA GO_REF:0000052 | ACCEPT | Summary: cytoplasmic ribonucleoprotein granule is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005515 protein binding | IPI PMID:15766526 Involvement of microRNA in AU-rich element-mediated mRNA ins... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:15766526 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0035196 miRNA processing | IMP PMID:22795694 Slicing-independent RISC activation requires the argonaute P... | ACCEPT | Summary: AGO4 participates in miRNA maturation by binding precursor-derived duplexes and promoting passenger-strand unwinding/ejection during RISC activation. Reason: QuickGO defines miRNA processing as generation of a functional miRNA and pre-miRNA processing as conversion to a mature miRNA molecule; neither is restricted to endonucleolytic cleavage. PMID:19966796 and PMID:22795694 demonstrate loading and slicing-independent maturation by Ago1/3/4. AGO4 supplies RNA binding and structural activity that performs part of this process, rather than merely being its substrate. This does not assign Drosha/Dicer catalysis to AGO4. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0031054 pre-miRNA processing | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: AGO4 participates in miRNA maturation by binding precursor-derived duplexes and promoting passenger-strand unwinding/ejection during RISC activation. Reason: QuickGO defines miRNA processing as generation of a functional miRNA and pre-miRNA processing as conversion to a mature miRNA molecule; neither is restricted to endonucleolytic cleavage. PMID:19966796 and PMID:22795694 demonstrate loading and slicing-independent maturation by Ago1/3/4. AGO4 supplies RNA binding and structural activity that performs part of this process, rather than merely being its substrate. This does not assign Drosha/Dicer catalysis to AGO4. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0003725 double-stranded RNA binding | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0003727 single-stranded RNA binding | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: AGO4 binds small-RNA duplexes during loading and retains a single-stranded guide in mature RISC. Reason: These are valid molecular-function descriptions at different levels of specificity. AGO4 retains RNA-binding domains and direct RISC-loading/unwinding evidence despite loss of slicer catalysis. Broadness and overlap with miRNA binding do not make this annotation an over-annotation. Supporting Evidence: PMID:19966796 all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes PMID:22795694 Thus, Ago1/3/4-ΞPAZ maintained their ability to physically associate with small-RNA duplexes, but not the ability to unwind and form active RISC. |
| GO:0016442 RISC complex | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: RISC complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0070578 RISC-loading complex | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: RISC-loading complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0070922 RISC complex assembly | IDA PMID:19966796 ATP-dependent human RISC assembly pathways. | ACCEPT | Summary: RISC complex assembly is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0090625 siRNA-mediated gene silencing by mRNA destabilization | IDA NOT PMID:15260970 Human Argonaute2 mediates RNA cleavage targeted by miRNAs an... | UNDECIDED | Summary: The source NOT assertion remains unresolved: cleavage-specific ontology wording and slicing-independent decay must be distinguished. Reason: Live QuickGO (2026-09-21) retains this BHF-UCL NOT|involved_in IDA row citing PMID:15260970, contrary to the new OpenScientist report's claim that no such negative annotation exists. GO:0090625 explicitly defines siRNA-directed target cleavage and cites PMID:15260970; its name alone cannot be read as a generic deadenylation process. The cached 2004 paper is abstract-only and establishes AGO2-specific endonuclease activity, which can support a cleavage-scoped negative. Full-text PMID:19838187 independently shows that tethered human AGO4 can promote biphasic deadenylation in mouse NIH3T3 cells; this establishes decay capacity but does not directly test natural guide-dependent recruitment or contradict a cleavage-specific NOT. Keep the original negation and UNDECIDED pending clarification of intended term scope and access to the original assay details. The report's blanket recommendation to move all negative claims to molecular function is not adopted. Supporting Evidence: PMID:15260970 endonuclease activity is exclusively associated with Ago2. PMID:18771919 the four tethered proteins caused nearly equal reductions in cytoplasmic mRNA concentration, suggesting that each has a similar capacity to destabilize mRNA. PMID:19383768 the N-terminal GW-repeat-containing regions of all three TNRC6s interact with the four human Argonaute proteins (AGO1-AGO4). PMID:19838187 all four human Ago proteins and TNRC6C are each able to recapitulate the two deadenylation steps. file:human/AGO4/AGO4-hypotheses/mrna-destabilization-versus-slicer-loss/openscientist.md Tethering bypasses guide:target recognition, and paralogs differ quantitatively. |
| GO:0005737 cytoplasm | IDA PMID:15260970 Human Argonaute2 mediates RNA cleavage targeted by miRNAs an... | ACCEPT | Summary: cytoplasm is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0016442 RISC complex | IDA PMID:15260970 Human Argonaute2 mediates RNA cleavage targeted by miRNAs an... | ACCEPT | Summary: RISC complex is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0035198 miRNA binding | IDA PMID:15260970 Human Argonaute2 mediates RNA cleavage targeted by miRNAs an... | ACCEPT | Summary: miRNA binding is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0035279 miRNA-mediated gene silencing by mRNA destabilization | IDA NOT PMID:15260970 Human Argonaute2 mediates RNA cleavage targeted by miRNAs an... | UNDECIDED | Summary: The source NOT assertion remains unresolved: cleavage-specific ontology wording and slicing-independent decay must be distinguished. Reason: Live QuickGO (2026-09-21) retains this BHF-UCL NOT|involved_in IDA row citing PMID:15260970, contrary to the new OpenScientist report's claim that no such negative annotation exists. GO:0035279 explicitly defines miRNA-directed endonucleolytic cleavage, although it also has related deadenylation synonyms. Those related synonyms do not by themselves override the definition. The cached 2004 paper is abstract-only and establishes AGO2-specific endonuclease activity, which can support a cleavage-scoped negative. Full-text PMID:19838187 independently shows that tethered human AGO4 can promote biphasic deadenylation in mouse NIH3T3 cells; this establishes decay capacity but does not directly test natural guide-dependent recruitment or contradict a cleavage-specific NOT. Keep the original negation and UNDECIDED pending clarification of intended term scope and access to the original assay details. The report's blanket recommendation to move all negative claims to molecular function is not adopted. Supporting Evidence: PMID:15260970 endonuclease activity is exclusively associated with Ago2. PMID:18771919 the four tethered proteins caused nearly equal reductions in cytoplasmic mRNA concentration, suggesting that each has a similar capacity to destabilize mRNA. PMID:19383768 the N-terminal GW-repeat-containing regions of all three TNRC6s interact with the four human Argonaute proteins (AGO1-AGO4). PMID:19838187 all four human Ago proteins and TNRC6C are each able to recapitulate the two deadenylation steps. file:human/AGO4/AGO4-hypotheses/mrna-destabilization-versus-slicer-loss/openscientist.md Tethering bypasses guide:target recognition, and paralogs differ quantitatively. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: membrane is a plausible or reported location/context but is not the core functional site annotation for AGO4. Reason: The core location is cytoplasmic RISC/RNP granules; nuclear, membrane, synaptic, exosomal, or other compartment annotations should remain non-core unless tied to a specific curated mechanism. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1606561 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1606682 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912362 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912363 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912364 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912366 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912367 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912368 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1912406 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2318752 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3209151 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-426489 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-426522 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4518575 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5687103 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8935766 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937097 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937134 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8938440 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8938487 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8938507 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8944650 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8944684 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8944706 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9011958 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9012203 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9012208 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9038545 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9618392 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9618486 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9624925 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9657791 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9858289 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9858309 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9924921 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9925095 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9925158 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9925159 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9925324 | ACCEPT | Summary: cytosol is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
| GO:0006402 mRNA catabolic process | IDA PMID:18771919 Importance of translation and nonnucleolytic ago proteins fo... | ACCEPT | Summary: AGO4 contributes to mRNA decay through its non-slicing RISC effector function. Reason: In PMID:18771919 each tethered human Argonaute, including AGO4, lowers reporter mRNA abundance; PMID:19383768 supplies a compatible TNRC6 recruitment mechanism. Target recognition and recruitment of the decay machinery constitute participation in mRNA catabolism. Lack of an endonuclease active site does not exclude this core effector role. Supporting Evidence: PMID:18771919 the four tethered proteins caused nearly equal reductions in cytoplasmic mRNA concentration, suggesting that each has a similar capacity to destabilize mRNA. PMID:19383768 the N-terminal GW-repeat-containing regions of all three TNRC6s interact with the four human Argonaute proteins (AGO1-AGO4). |
| GO:0035278 miRNA-mediated gene silencing by inhibition of translation | IDA PMID:18771919 Importance of translation and nonnucleolytic ago proteins fo... | ACCEPT | Summary: miRNA-mediated gene silencing by inhibition of translation is consistent with AGO4 as a small-RNA-loaded Argonaute/RISC effector. Reason: The falcon report supports AGO4 function in miRISC-mediated small-RNA-guided repression and related RISC complexes or cytoplasmic RNP compartments. Supporting Evidence: file:human/AGO4/AGO4-deep-research-falcon.md Human AGO4 (EIF2C4; UniProt Q9HCK5) is best supported (in the retrieved literature set) as a **small-RNA-binding Argonaute paralog** that contributes to gene regulation largely through **non-slicing mechanisms** |
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Download this section (compressed HTML)Q: Which endogenous human tissues or stress states require AGO4-specific RISC activity rather than redundant activity from other AGO paralogs?
Q: Which protein cofactors determine guide loading, localization, and non-core nuclear or granule-associated functions of AGO4?
Q: Do GO:0035279 and GO:0090625 formally denote cleavage-specific pathways despite their destabilization names, and should their original AGO4 NOT assertions be retained on that scope? GO:0035279 also has related deadenylation synonyms; clarification should distinguish this from the verified tethering-based decay capacity.
Experiment: Endogenous tagging of AGO4 followed by small-RNA CLIP, target RNA profiling, and paralog-specific rescue in AGO-depleted human cells.
Hypothesis: AGO4 has paralog-specific guide, target, and compartment preferences within human RISC biology.
Type: genome editing/RNA-protein interaction profiling
Experiment: Biochemical reconstitution of AGO4-RISC with representative miRNA and siRNA guides to compare target repression, target cleavage, and TNRC6 recruitment.
Hypothesis: AGO4 activity is best explained by guide-loaded RISC function rather than generic RNA or protein binding.
Type: biochemical reconstitution
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