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.
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.
Parent term: ERAD pathway
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; the core compartment and site of action for RNF170. Reason: Correct core localization; RNF170 is a multi-pass ER membrane protein supported experimentally (IDA, PMID:31076723; PMID:21610068). Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:21610068, ECO:0000269|PubMed:31076723} |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic assignment of RING-type ubiquitin ligase activity, the core molecular function of RNF170. Reason: Correct core molecular function; supported by IDA (PMID:31076723), EC 2.3.2.27, and RING-region catalytic residues (C102S/H104A abolishes activity). Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt EC=2.3.2.27 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Interactome interaction with the proteasome subunit PSMA6, consistent with RNF170's role in proteasomal degradation. Bare protein binding is uninformative. Reason: Records a real interaction (PSMA6) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt Q96K19; P60900: PSMA6 |
| GO:0005515 protein binding | IPI Q96K19-5 PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Isoform-5 binary interactome interactions (e.g. SGTA, STARD3, TMEM109). Bare protein binding is uninformative; isoform 5 is a truncated splice variant. Reason: High-throughput interactions on a truncated isoform; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt Q96K19-5; O43765: SGTA |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific ERAD/degradative ubiquitination RNF170 performs. Reason: Correct but generic; the specific ERAD/IP3R degradation and K48-ubiquitination annotations better capture the role. Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:31076723 E3 ubiquitin ligase RNF170 inhibits innate immune responses ... | ACCEPT | Summary: Direct experimental evidence that RNF170 acts at the ER membrane (TLR3 study); the core compartment for its ligase function. Reason: Core localization/site of action with direct experimental support. Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:21610068, ECO:0000269|PubMed:31076723} |
| GO:0034140 negative regulation of toll-like receptor 3 signaling pathway | IDA PMID:31076723 E3 ubiquitin ligase RNF170 inhibits innate immune responses ... | KEEP AS NON CORE | Summary: Direct evidence that RNF170 negatively regulates TLR3 signaling by degrading TLR3; a real but secondary immune-regulatory role. Reason: Well supported (PMID:31076723, mainly murine cells) but a secondary role distinct from the core IP3R-ERAD function. Supporting Evidence: PMID:31076723 The genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:31076723 E3 ubiquitin ligase RNF170 inhibits innate immune responses ... | ACCEPT | Summary: Direct experimental demonstration of RNF170 RING-dependent ubiquitin ligase activity (K48 ubiquitination of TLR3). Core molecular function. Reason: Core molecular function with direct experimental (IDA) support; RING catalytic mutations (C102S/H104A) abolish activity. Supporting Evidence: PMID:31076723 RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:31076723 E3 ubiquitin ligase RNF170 inhibits innate immune responses ... | ACCEPT | Summary: Direct evidence that RNF170 builds K48-linked (degradative) polyubiquitin chains, demonstrated on TLR3. This degradative topology also underlies its IP3R/ERAD role. Reason: Directly demonstrated K48-linked ubiquitination, the canonical degradative topology underlying RNF170's substrate-degradation functions. Supporting Evidence: PMID:31076723 RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 |
| GO:0036503 ERAD pathway | IDA PMID:21610068 RNF170 protein, an endoplasmic reticulum membrane ubiquitin ... | NEW | 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. 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. Supporting Evidence: file:human/RNF170/RNF170-uniprot.txt E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation |
Loading supporting content…
Download this section (compressed HTML)Q: 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?
Q: How do SPG85/SNAX1 RING-region variants (e.g. C102R, R199C) mechanistically impair RNF170 ligase activity and IP3R/calcium homeostasis to cause neurodegeneration?
Experiment: 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.
Experiment: 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.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)