UNC93B1 is a polytopic (twelve-transmembrane) endoplasmic reticulum membrane protein of the unc-93 family that acts as a dedicated chaperone and trafficking factor for the nucleotide-sensing Toll-like receptors. It physically binds the transmembrane and juxtamembrane regions of TLR3, TLR7, TLR8 and TLR9 in the ER and delivers them through the secretory pathway to endolysosomal compartments, where the receptors encounter nucleic-acid ligands and signal; it also relocalizes from the ER to endosomes and lysosomes upon stimulation. Its architecture resembles the major facilitator superfamily transporters, and cryo-EM structures show TLR ectodomains and transmembrane regions docking onto its N-terminal helical bundle. UNC93B1 is required for the signalling of all endosomal TLRs, but it is dispensable for ligand recognition and signal initiation by the receptors themselves, acting upstream to position and regulate them rather than transducing the signal. Beyond the endosomal TLRs it is also needed for plasma-membrane localization and signalling of the cell-surface flagellin receptor TLR5. By compartmentalizing nucleic-acid-sensing TLRs it both enables antimicrobial and antiviral innate immunity and limits inappropriate recognition of self nucleic acids. Loss-of-function mutations cause autosomal recessive UNC93B1 deficiency, which predisposes to herpes simplex encephalitis through impaired type I and type III interferon responses. Conversely, UNC93B1 also restrains signalling after delivery (particularly by TLR7 and TLR8), and rare missense variants in its negative regulatory regions cause monogenic systemic lupus erythematosus, chilblain lupus and related autoimmune or inflammatory disease through enhanced TLR7 and/or TLR8 responses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678927 | ACCEPT | Summary: UNC93B1 transits the Golgi en route from the ER to endolysosomes during TLR trafficking (Reactome TAS). Reason: Consistent with the conventional secretory route by which UNC93B1 chaperones TLRs from ER through Golgi to endolysosomes; a transit location, non-core. Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: UNC93B1 transits the Golgi en route from the ER to endolysosomes during TLR trafficking (Reactome TAS). Reason: Consistent with the conventional secretory route by which UNC93B1 chaperones TLRs from ER through Golgi to endolysosomes; a transit location, non-core. Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: General toll-like receptor signalling pathway (InterPro2GO from the UNC93B1 signature). UNC93B1 is required for endosomal TLR signalling but acts upstream as a trafficking chaperone. Reason: UNC93B1 is necessary for TLR3/7/8/9 signalling, but it does not perform a step of signal transduction (it is dispensable for ligand recognition and signal initiation). Its role is upstream receptor trafficking, so the pathway term is retained as non-core rather than as the core function. Supporting Evidence: PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 |
| GO:0005515 protein binding | IPI PMID:22164301 UNC93B1 physically associates with human TLR8 and regulates ... | MODIFY | Summary: IPI with TLR8 (Q9NR97). UNC93B1 physically associates with human TLR8 and is critical for TLR8 signalling. Reason: Generic protein binding is uninformative, but the partner is a Toll-like receptor, so the interaction is captured by the specific and already-supported Toll-like receptor binding term. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:22164301 UNC93B1 physically associated with human TLR8, similar to TLRs 3, 7, and 9, and played a critical role in TLR8-mediated signaling |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: IPI with UniProtKB:P55060 from an interferon-stimulated-gene AP-MS interaction network. Reason: Generic protein binding is uninformative and this partner (a nuclear-transport factor) has no established functional role with UNC93B1; from a large-scale screen without dedicated follow-up. |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: IPI with UniProtKB:Q14974 from an interferon-stimulated-gene AP-MS interaction network. Reason: Generic protein binding is uninformative and this partner (a nuclear-transport factor) has no established functional role with UNC93B1; from a large-scale screen without dedicated follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:A8MZ59 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:O14843 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:O60883 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:O95471 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:P11912 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:P26715 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q15125 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q5T700 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q8NFU1 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q8WV48 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q8WWF3 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q969F0 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q96BA8 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q96CE8 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q96P66 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q96Q45-2 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9GZY8-5 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9H400 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9H7V2 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9H902 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9NQQ7-3 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9NZD1 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9UM44 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with UniProtKB:Q9Y282 from a high-throughput yeast two-hybrid binary interactome (HuRI). No dedicated functional characterization of this UNC93B1 interaction is reported. Reason: Generic protein binding is uninformative, and this partner comes from a proteome-scale binary screen with no functional follow-up specific to UNC93B1. Removal does not assert the interaction is false; it removes an uninformative annotation. |
| GO:0005515 protein binding | IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV... | REMOVE | Summary: IPI with SARS-CoV-2 ORF7b (P0DTD8) from a virus-host multilevel proteomics screen. Reason: Generic protein binding is uninformative; a xeno viral-protein interaction from a proteomics screen does not describe a UNC93B1 molecular function. Removal does not assert the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI with TLR8 (Q9NR97) from a proteome-scale AP-MS interactome. The partner is a Toll-like receptor. Reason: Generic protein binding is uninformative; because the detected partner is a TLR, the informative representation is Toll-like receptor binding, consistent with UNC93B1 biology. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:22164301 UNC93B1 physically associated with human TLR8, similar to TLRs 3, 7, and 9, and played a critical role in TLR8-mediated signaling |
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: UNC93B1 is active in / localizes to the lysosome, the endpoint of the ER-to-endolysosome trafficking route it drives for nucleotide-sensing TLRs. Reason: Consistent with UNC93B1 delivering TLRs to endolysosomes and relocalizing there upon stimulation. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: UNC93B1 is active in / localizes to the lysosome, the endpoint of the ER-to-endolysosome trafficking route it drives for nucleotide-sensing TLRs. Reason: Consistent with UNC93B1 delivering TLRs to endolysosomes and relocalizing there upon stimulation. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: UNC93B1 is active in / localizes to the lysosome, the endpoint of the ER-to-endolysosome trafficking route it drives for nucleotide-sensing TLRs. Reason: Consistent with UNC93B1 delivering TLRs to endolysosomes and relocalizing there upon stimulation. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005768 endosome | IBA GO_REF:0000033 | ACCEPT | Summary: UNC93B1 is active in / localizes to the endosome, part of the endolysosomal compartment to which it delivers nucleotide-sensing TLRs. Reason: Consistent with the ER-to-endosome trafficking function; endosomal localization is well established (deferring to the IDA curator for PMID:21642595, which is abstract-only in the cache). Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005768 endosome | IDA PMID:21642595 BAD-LAMP is a novel biomarker of nonactivated human plasmacy... | ACCEPT | Summary: UNC93B1 is active in / localizes to the endosome, part of the endolysosomal compartment to which it delivers nucleotide-sensing TLRs. Reason: Consistent with the ER-to-endosome trafficking function; endosomal localization is well established (deferring to the IDA curator for PMID:21642595, which is abstract-only in the cache). Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005768 endosome | IEA GO_REF:0000120 | ACCEPT | Summary: UNC93B1 is active in / localizes to the endosome, part of the endolysosomal compartment to which it delivers nucleotide-sensing TLRs. Reason: Consistent with the ER-to-endosome trafficking function; endosomal localization is well established (deferring to the IDA curator for PMID:21642595, which is abstract-only in the cache). Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005768 endosome | ISS GO_REF:0000024 | ACCEPT | Summary: UNC93B1 is active in / localizes to the endosome, part of the endolysosomal compartment to which it delivers nucleotide-sensing TLRs. Reason: Consistent with the ER-to-endosome trafficking function; endosomal localization is well established (deferring to the IDA curator for PMID:21642595, which is abstract-only in the cache). Supporting Evidence: PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0005783 endoplasmic reticulum | IDA PMID:18082565 Assessing the function of human UNC-93B in Toll-like recepto... | ACCEPT | Summary: UNC93B1 is an ER-resident membrane protein; it interacts with nucleotide-sensing TLRs in the ER before trafficking them. Reason: Direct evidence for ER localization; this is the core resting location of UNC93B1. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) PMID:18082565 it localizes to the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IDA PMID:21642595 BAD-LAMP is a novel biomarker of nonactivated human plasmacy... | ACCEPT | Summary: UNC93B1 is an ER-resident membrane protein; it interacts with nucleotide-sensing TLRs in the ER before trafficking them. Reason: Direct evidence for ER localization; this is the core resting location of UNC93B1. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) PMID:18082565 it localizes to the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: UNC93B1 is an ER-resident membrane protein; it interacts with nucleotide-sensing TLRs in the ER before trafficking them. Reason: Direct evidence for ER localization; this is the core resting location of UNC93B1. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) PMID:18082565 it localizes to the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UNC93B1 is an ER membrane (multi-pass) protein. Reason: Consistent with UNC93B1 being a polytopic ER membrane protein that interacts with TLR transmembrane domains in the ER. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678921 | ACCEPT | Summary: UNC93B1 is an ER membrane (multi-pass) protein. Reason: Consistent with UNC93B1 being a polytopic ER membrane protein that interacts with TLR transmembrane domains in the ER. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: UNC93B1 is an ER membrane (multi-pass) protein. Reason: Consistent with UNC93B1 being a polytopic ER membrane protein that interacts with TLR transmembrane domains in the ER. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5607838 | ACCEPT | Summary: UNC93B1 is an ER membrane (multi-pass) protein. Reason: Consistent with UNC93B1 being a polytopic ER membrane protein that interacts with TLR transmembrane domains in the ER. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) |
| GO:0006886 intracellular protein transport | IBA GO_REF:0000033 | ACCEPT | Summary: UNC93B1 mediates intracellular transport of nucleotide-sensing TLRs from the ER to endolysosomes. Reason: This is a core process for UNC93B1: it delivers TLR7/TLR9 (and TLR3/TLR8) from the ER to endolysosomes and is indispensable for their trafficking. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome file:human/UNC93B1/UNC93B1-deep-research-falcon.md The protein acts as an essential trafficking factor that mediates the exit of TLR3, TLR7, TLR8, and TLR9 from the endoplasmic reticulum (ER) and their subsequent delivery to endosomal compartments |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000107 | ACCEPT | Summary: UNC93B1 mediates intracellular transport of nucleotide-sensing TLRs from the ER to endolysosomes. Reason: This is a core process for UNC93B1: it delivers TLR7/TLR9 (and TLR3/TLR8) from the ER to endolysosomes and is indispensable for their trafficking. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome |
| GO:0006886 intracellular protein transport | ISS GO_REF:0000024 | ACCEPT | Summary: UNC93B1 mediates intracellular transport of nucleotide-sensing TLRs from the ER to endolysosomes. Reason: This is a core process for UNC93B1: it delivers TLR7/TLR9 (and TLR3/TLR8) from the ER to endolysosomes and is indispensable for their trafficking. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes PMID:33432245 indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome |
| GO:0032009 early phagosome | IEA GO_REF:0000107 | ACCEPT | Summary: Early phagosome localization (ortholog/subcellular-location mapping from mouse Unc93b1). Reason: Consistent with UNC93B1 acting in the endosomal/phagosomal system; a peripheral, non-core location transferred from the mouse ortholog. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0032009 early phagosome | ISS GO_REF:0000024 | ACCEPT | Summary: Early phagosome localization (ortholog/subcellular-location mapping from mouse Unc93b1). Reason: Consistent with UNC93B1 acting in the endosomal/phagosomal system; a peripheral, non-core location transferred from the mouse ortholog. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
| GO:0034138 toll-like receptor 3 signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Toll-like receptor 3 signaling pathway. UNC93B1 is required for TLR3 signalling because it delivers TLR3 to the endolysosome; it does not itself transduce the TLR3 signal. Reason: UNC93B1 is necessary for TLR3 signalling (knockdown/mutation abolishes it) but acts upstream as a trafficking chaperone and is dispensable for ligand recognition and signal initiation. Retained as non-core per the participation distinction; not removed, deferring to the experimental curation (human IMP and PANTHER IBD node). Supporting Evidence: PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034138 toll-like receptor 3 signaling pathway | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Toll-like receptor 3 signaling pathway. UNC93B1 is required for TLR3 signalling because it delivers TLR3 to the endolysosome; it does not itself transduce the TLR3 signal. Reason: UNC93B1 is necessary for TLR3 signalling (knockdown/mutation abolishes it) but acts upstream as a trafficking chaperone and is dispensable for ligand recognition and signal initiation. Retained as non-core per the participation distinction; not removed, deferring to the experimental curation (human IMP and PANTHER IBD node). Supporting Evidence: PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034138 toll-like receptor 3 signaling pathway | IMP PMID:18082565 Assessing the function of human UNC-93B in Toll-like recepto... | KEEP AS NON CORE | Summary: Toll-like receptor 3 signaling pathway. UNC93B1 is required for TLR3 signalling because it delivers TLR3 to the endolysosome; it does not itself transduce the TLR3 signal. Reason: UNC93B1 is necessary for TLR3 signalling (knockdown/mutation abolishes it) but acts upstream as a trafficking chaperone and is dispensable for ligand recognition and signal initiation. Retained as non-core per the participation distinction; not removed, deferring to the experimental curation (human IMP and PANTHER IBD node). Supporting Evidence: PMID:18082565 it localizes to the endoplasmic reticulum PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034154 toll-like receptor 7 signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Toll-like receptor 7 signaling pathway. UNC93B1 is required for TLR7 signalling via ER-to-endolysosome delivery of TLR7; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR7 signalling (UNC-93B-deficient cells are unresponsive to TLR7) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation. Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034154 toll-like receptor 7 signaling pathway | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Toll-like receptor 7 signaling pathway. UNC93B1 is required for TLR7 signalling via ER-to-endolysosome delivery of TLR7; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR7 signalling (UNC-93B-deficient cells are unresponsive to TLR7) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation. Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034154 toll-like receptor 7 signaling pathway | IMP PMID:19006693 IRAK-4- and MyD88-dependent pathways are essential for the r... | KEEP AS NON CORE | Summary: Toll-like receptor 7 signaling pathway. UNC93B1 is required for TLR7 signalling via ER-to-endolysosome delivery of TLR7; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR7 signalling (UNC-93B-deficient cells are unresponsive to TLR7) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation. Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:18305481 UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs |
| GO:0034162 toll-like receptor 9 signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Toll-like receptor 9 signaling pathway. UNC93B1 is required for TLR9 signalling via ER-to-endolysosome delivery of TLR9; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR9 signalling (UNC-93B-deficient cells are unresponsive to TLR9; mouse 3d mutation abolishes TLR9 signalling) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation and the GO-CAM model (65a1f4f800002740). Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:16415873 no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 |
| GO:0034162 toll-like receptor 9 signaling pathway | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Toll-like receptor 9 signaling pathway. UNC93B1 is required for TLR9 signalling via ER-to-endolysosome delivery of TLR9; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR9 signalling (UNC-93B-deficient cells are unresponsive to TLR9; mouse 3d mutation abolishes TLR9 signalling) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation and the GO-CAM model (65a1f4f800002740). Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:16415873 no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 |
| GO:0034162 toll-like receptor 9 signaling pathway | IMP PMID:19006693 IRAK-4- and MyD88-dependent pathways are essential for the r... | KEEP AS NON CORE | Summary: Toll-like receptor 9 signaling pathway. UNC93B1 is required for TLR9 signalling via ER-to-endolysosome delivery of TLR9; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR9 signalling (UNC-93B-deficient cells are unresponsive to TLR9; mouse 3d mutation abolishes TLR9 signalling) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation and the GO-CAM model (65a1f4f800002740). Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:16415873 no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 |
| GO:0034162 toll-like receptor 9 signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Toll-like receptor 9 signaling pathway. UNC93B1 is required for TLR9 signalling via ER-to-endolysosome delivery of TLR9; it does not transduce the signal itself. Reason: UNC93B1 is necessary for TLR9 signalling (UNC-93B-deficient cells are unresponsive to TLR9; mouse 3d mutation abolishes TLR9 signalling) but acts upstream as a trafficking chaperone, dispensable for signal initiation. Retained as non-core; not removed, deferring to experimental curation and the GO-CAM model (65a1f4f800002740). Supporting Evidence: PMID:19006693 UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9 PMID:16415873 no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 |
| GO:0035325 Toll-like receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Toll-like receptor binding: UNC93B1 physically binds the transmembrane/juxtamembrane regions of TLR3, TLR7, TLR8 and TLR9 (and TLR5). Reason: Core molecular function of UNC93B1, supported by direct interaction and cryo-EM structural data. This receptor-binding activity underlies its chaperone/trafficking role. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions |
| GO:0035325 Toll-like receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Toll-like receptor binding: UNC93B1 physically binds the transmembrane/juxtamembrane regions of TLR3, TLR7, TLR8 and TLR9 (and TLR5). Reason: Core molecular function of UNC93B1, supported by direct interaction and cryo-EM structural data. This receptor-binding activity underlies its chaperone/trafficking role. Supporting Evidence: PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions |
| GO:0035325 Toll-like receptor binding | IPI PMID:33432245 Cryo-EM structures of Toll-like receptors in complex with UN... | ACCEPT | Summary: Toll-like receptor binding: UNC93B1 physically binds the transmembrane/juxtamembrane regions of TLR3, TLR7, TLR8 and TLR9 (and TLR5). Reason: Core molecular function of UNC93B1, supported by direct interaction and cryo-EM structural data. This receptor-binding activity underlies its chaperone/trafficking role. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:18305481 essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER) |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: Phagocytic vesicle localization (UniProt subcellular-location mapping). Reason: Consistent with UNC93B1 acting in the endosomal/phagosomal system; a peripheral, non-core location. Supporting Evidence: PMID:18305481 function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes |
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Download this section (compressed HTML)Q: Should a dedicated trafficking chaperone such as UNC93B1 be annotated as involved_in the downstream TLR signaling pathways it enables, or is acts_upstream_of / a protein-carrier + trafficking representation more accurate?
Q: What structural features of UNC93B1 determine its selectivity among TLR7, TLR9 and the cell-surface receptor TLR5, and how is the TLR9-over-TLR7 trafficking preference set?
Q: How does UNC93B1 balance enabling antimicrobial nucleic-acid sensing against restraining recognition of self nucleic acids, and how do disease-associated variants shift that balance?
Q: Should UNC93B1-dependent negative regulation of TLR7/TLR8 signalling (syntenin-1-mediated sorting of TLR7 into multivesicular bodies; gain-of-function lupus variants in negative regulatory regions, PMID:38780621, PMID:38869500) be represented with a negative-regulation process term, and is the same true for its reported attenuation of cGAS-STING signalling via lysosomal delivery of STING (PMID:35577759, single-laboratory report)?
Experiment: Cryo-EM of UNC93B1 bound to TLR5 and to TLR9 to define the structural basis of its differential targeting to the plasma membrane versus endolysosomes
Experiment: Proximity-labeling proteomics (e.g. BioID/APEX) along the ER-to-endolysosome route to distinguish functional trafficking partners from high-throughput binary-interactome noise
Experiment: Separation-of-function UNC93B1 mutants that retain TLR binding but fail trafficking, to test whether receptor binding alone contributes to TLR signalling independent of delivery
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