id: Q96K19 gene_symbol: RNF170 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- RNF170 is a multi-pass endoplasmic reticulum membrane RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27, 258 aa) with three transmembrane helices and a large cytoplasmic loop carrying a C3HC4 RING domain (catalytic Cys-102/His-104). Its defining function is in ER-associated degradation (ERAD) of the inositol 1,4,5-trisphosphate receptor (ITPR1/IP3R): RNF170 is essential for stimulus-induced ubiquitination and degradation of activated ITPR1 and also contributes to ITPR1 turnover in resting cells, thereby controlling IP3R abundance and ER calcium-release signaling. To do this it is constitutively associated with the ERLIN1/ERLIN2 (SPFH-domain) complex, which recognizes activated IP3R and recruits RNF170 to ubiquitinate it. RNF170 also has a secondary, ligase-dependent immune-regulatory role: it binds Toll-like receptor 3 (TLR3) and builds K48-linked polyubiquitin chains on Lys-766 in the TLR3 TIR domain to drive its proteasomal degradation, selectively dampening TLR3-triggered innate immune responses. RNF170 is broadly expressed (including spinal cord); loss-of-function and RING-region missense variants cause autosomal dominant sensory ataxia (SNAX1) and autosomal recessive hereditary spastic paraplegia (SPG85), linking its ER ubiquitin-ligase activity to neuronal homeostasis. Its core localization and site of action is the ER membrane. alternative_products: - name: '1' id: Q96K19-1 - name: '2' id: Q96K19-2 sequence_note: VSP_023856 - name: '3' id: Q96K19-3 sequence_note: VSP_023855, VSP_023857 - name: '4' id: Q96K19-4 sequence_note: VSP_023851, VSP_023852 - name: '5' id: Q96K19-5 sequence_note: VSP_023853, VSP_023854 - name: '6' id: Q96K19-6 sequence_note: VSP_044556 existing_annotations: - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; the core compartment and site of action for RNF170. action: ACCEPT reason: Correct core localization; RNF170 is a multi-pass ER membrane protein supported experimentally (IDA, PMID:31076723; PMID:21610068). supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:21610068, ECO:0000269|PubMed:31076723}' - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Combined automated electronic assignment of RING-type ubiquitin ligase activity, the core molecular function of RNF170. action: ACCEPT reason: Correct core molecular function; supported by IDA (PMID:31076723), EC 2.3.2.27, and RING-region catalytic residues (C102S/H104A abolishes activity). supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: EC=2.3.2.27 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Interactome interaction with the proteasome subunit PSMA6, consistent with RNF170's role in proteasomal degradation. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (PSMA6) but bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: 'Q96K19; P60900: PSMA6' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables isoform: Q96K19-5 review: summary: Isoform-5 binary interactome interactions (e.g. SGTA, STARD3, TMEM109). Bare protein binding is uninformative; isoform 5 is a truncated splice variant. action: KEEP_AS_NON_CORE reason: High-throughput interactions on a truncated isoform; bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: 'Q96K19-5; O43765: SGTA' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process, a parent of the specific ERAD/degradative ubiquitination RNF170 performs. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific ERAD/IP3R degradation and K48-ubiquitination annotations better capture the role. supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IDA original_reference_id: PMID:31076723 qualifier: is_active_in review: summary: Direct experimental evidence that RNF170 acts at the ER membrane (TLR3 study); the core compartment for its ligase function. action: ACCEPT reason: Core localization/site of action with direct experimental support. supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000269|PubMed:21610068, ECO:0000269|PubMed:31076723}' - term: id: GO:0034140 label: negative regulation of toll-like receptor 3 signaling pathway evidence_type: IDA original_reference_id: PMID:31076723 qualifier: involved_in review: summary: Direct evidence that RNF170 negatively regulates TLR3 signaling by degrading TLR3; a real but secondary immune-regulatory role. action: KEEP_AS_NON_CORE reason: Well supported (PMID:31076723, mainly murine cells) but a secondary role distinct from the core IP3R-ERAD function. supported_by: - reference_id: PMID:31076723 supporting_text: The genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:31076723 qualifier: enables review: summary: Direct experimental demonstration of RNF170 RING-dependent ubiquitin ligase activity (K48 ubiquitination of TLR3). Core molecular function. action: ACCEPT reason: Core molecular function with direct experimental (IDA) support; RING catalytic mutations (C102S/H104A) abolish activity. supported_by: - reference_id: PMID:31076723 supporting_text: RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 - term: id: GO:0070936 label: protein K48-linked ubiquitination evidence_type: IDA original_reference_id: PMID:31076723 qualifier: involved_in review: summary: Direct evidence that RNF170 builds K48-linked (degradative) polyubiquitin chains, demonstrated on TLR3. This degradative topology also underlies its IP3R/ERAD role. action: ACCEPT reason: Directly demonstrated K48-linked ubiquitination, the canonical degradative topology underlying RNF170's substrate-degradation functions. supported_by: - reference_id: PMID:31076723 supporting_text: RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 - term: id: GO:0036503 label: ERAD pathway evidence_type: IDA original_reference_id: PMID:21610068 qualifier: involved_in review: summary: RNF170 mediates ubiquitination and ERAD-dependent degradation of activated ITPR1/IP3R, its defining function (Lu et al. 2011). This core process is currently absent from the GOA and is proposed as a NEW annotation. action: NEW reason: The IP3R/ITPR1 ERAD role with the ERLIN1/ERLIN2 complex is well established experimentally but not represented in the current GOA; it should be added. supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation - reference_id: PMID:31636353 references: - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:21610068 title: 'RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.' findings: - statement: RNF170 is an ER-membrane ubiquitin ligase that, constitutively associated with the ERLIN1/ERLIN2 complex, mediates ubiquitination and ERAD-dependent degradation of activated inositol 1,4,5-trisphosphate receptor (ITPR1/IP3R). reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (J Biol Chem 286:24426-24433). Founding/defining study of RNF170 as the IP3R ERAD ligase and ERLIN1/ERLIN2 partner; not cached in publications/, supporting text taken from the UniProt record. This core IP3R-ERAD role is currently absent from the GOA. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of the PSMA6 (proteasome subunit) protein binding annotation. - id: PMID:31076723 title: E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting and degrading TLR3 in murine cells. findings: - statement: RNF170 binds TLR3 and catalyzes K48-linked polyubiquitination of Lys-766 in the TLR3 TIR domain, promoting proteasomal degradation of TLR3 and selectively inhibiting TLR3-triggered innate immune responses; RNF170 acts at the ER membrane and its ligase activity requires RING residues Cys-102/His-104. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; source of the IDA ligase-activity, ER-membrane, K48-ubiquitination and negative-regulation-of-TLR3 annotations. Predominantly murine cells. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of isoform-5 (Q96K19-5) bare protein binding annotations. - id: PMID:31636353 title: Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. findings: - statement: Bi-allelic (recessive) RNF170 variants cause autosomal recessive hereditary spastic paraplegia (SPG85) in four unrelated families; functional studies in patient fibroblasts, mutant SH-SY5Y cells and zebrafish knockdown link the loss of RNF170-mediated ITPR1/IP3R degradation (ERAD) and altered ER calcium signaling to the disease. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Nat Commun 2019;10(1):4790; DOI 10.1038/s41467-019-12620-9; PMC6803694). Falcon deep-research finding. Primary genetics study establishing recessive RNF170 variants as a cause of HSP (SPG85) and tying the phenotype to the IP3R/ITPR1 ERAD pathway. Not cached in publications/, so no verbatim supporting_text added to annotations. - id: PMID:38782601 title: ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway. findings: - statement: ERLIN1/2 ring-like SPFH-domain scaffolds bind a conserved luminal N-terminal motif shared by RNF170 and the full-length isoform of TMUB1, bridging the two proteins in cholesterol-rich ER nanodomains; variants that preclude these interactions have been linked to hereditary spastic paraplegia, and ERLIN scaffolds limit cholesterol esterification to favour ER-to-Golgi cholesterol transport and regulate the secretory pathway. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Life Sci Alliance 2024;7(8):e202402620; DOI 10.26508/lsa.202402620). Falcon deep-research finding. Defines a luminal N-terminal motif by which the ERLIN1/2 scaffold engages RNF170 (and TMUB1-L), extending the ERLIN-RNF170 module to cholesterol/secretory-pathway regulation. Not cached in publications/, so no verbatim supporting_text added to annotations. core_functions: - description: ER-membrane RING-type E3 ubiquitin ligase that ubiquitinates the activated inositol 1,4,5-trisphosphate receptor (ITPR1/IP3R) to drive its ERAD-mediated degradation, acting as the catalytic partner of the ERLIN1/ERLIN2 complex to control IP3R abundance and ER calcium signaling. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: Constitutively associated with the ERLIN1/ERLIN 2 complex - reference_id: PMID:38782601 directly_involved_in: - id: GO:0036503 label: ERAD pathway - description: ER-membrane ubiquitin ligase that builds K48-linked polyubiquitin chains on Toll-like receptor 3 (TLR3) to promote its proteasomal degradation, negatively regulating TLR3-triggered innate immune signaling. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:31076723 supporting_text: RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 and promoted the degradation of TLR3 through the proteasome pathway directly_involved_in: - id: GO:0034140 label: negative regulation of toll-like receptor 3 signaling pathway proposed_new_terms: - proposed_name: inositol 1,4,5-trisphosphate receptor catabolic process via the ERAD pathway proposed_definition: The chemical reactions and pathways resulting in the breakdown of an inositol 1,4,5-trisphosphate receptor (IP3R/ITPR), in which the activated receptor is ubiquitinated at the endoplasmic reticulum membrane and degraded via the ER-associated degradation (ERAD) pathway and the proteasome. justification: RNF170's defining, experimentally established function is the ERLIN1/ERLIN2-coupled ubiquitination and ERAD-mediated degradation of activated ITPR1/IP3R, which is currently not captured by any specific GO term in the GOA (only the generic ERAD pathway, GO:0036503, exists). A substrate-specific child term would better represent this well-characterized biology. proposed_parent: id: GO:0036503 label: ERAD pathway supported_by: - reference_id: file:human/RNF170/RNF170-uniprot.txt supporting_text: E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation suggested_questions: - question: Is the core IP3R/ITPR1 ERAD function (with the ERLIN1/ERLIN2 complex) conserved in human cells as established in the original studies, and should it be added to the GOA given that it is currently absent? - question: How do SPG85/SNAX1 RING-region variants (e.g. C102R, R199C) mechanistically impair RNF170 ligase activity and IP3R/calcium homeostasis to cause neurodegeneration? suggested_experiments: - description: Reconstitute or immunoprecipitate the RNF170-ERLIN1-ERLIN2 complex and assay stimulus-induced ITPR1 ubiquitination and degradation in WT vs RING-mutant (C102S/H104A) and SPG85-variant RNF170 to map the substrate lysines and chain topology on IP3R. - description: Perform RNF170 knockout/rescue in neuronal cells with ER calcium imaging and quantitative proteomics to test whether IP3R stabilization and altered Ca2+ signaling underlie the sensory ataxia and spastic paraplegia phenotypes.