RNF170

RNF170 is an endoplasmic reticulum membrane-resident RING-domain E3 ubiquitin ligase that controls protein turnover at the ER and thereby shapes intracellular Ca2+ signaling and innate immune output (PMID:21610068, PMID:31076723). Its founding function is the regulated degradation of activated IP3 receptors: a constitutive pool of RNF170 is bound to the ERLIN1/2 (SPFH1/2) scaffold complex, which recruits the ligase to stimulated IP3 receptors and enables their ubiquitination and proteasomal clearance (PMID:21610068). RNF170 mediates the full repertoire of ubiquitin conjugates added to activated IP3 receptors, including monoubiquitin and K48- and K63-linked chains (PMID:25882839). Protein stability is governed by ionic interactions between charged transmembrane residues and by a conserved luminal N-terminal region that docks onto the SPFH domain of adjacent ERLIN subunits, an interface also used by TMUB1 (PMID:25882839, PMID:38782601). Beyond Ca2+ control, RNF170 binds TLR3 and catalyzes K48-linked polyubiquitination at K766 in the TIR domain to drive TLR3 proteasomal degradation, restraining TLR3-triggered IRF3 and NF-κB signaling (PMID:31076723), and it (with RNF149) ubiquitinates DEK at K349 to suppress the RIPK1-PANoptosis pathway (PMID:40120540). Bi-allelic loss-of-function or destabilizing mutations in RNF170 cause autosomal recessive hereditary spastic paraplegia and sensory ataxia, with disease-associated alleles either enhancing RNF170 autoubiquitination/degradation or abolishing protein expression (PMID:25882839, PMID:31636353, PMID:36046950).

1. 2011 High

   Established RNF170 as the ER E3 ligase that ubiquitinates activated IP3 receptors and defined how it reaches its substrate, answering how stimulated IP3 receptors are targeted for degradation.

   Evidence Co-IP, RNAi knockdown, catalytically inactive mutant overexpression, and subcellular fractionation in cultured cells

   PMID:21610068

   Open questions at the time

   • Did not define which ubiquitin linkage types RNF170 builds on the receptor
   • Mechanism by which ERLIN1/2 senses receptor activation to recruit RNF170 not resolved
2. 2015 High

   Linked a disease mutation to RNF170 protein instability and showed RNF170 is responsible for all ubiquitin conjugate types on activated IP3 receptors, connecting ligase activity to a functional Ca2+ defect.

   Evidence Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca2+ mobilization assays, and Western blot in ADSA patient-derived lymphoblasts

   PMID:25882839

   Open questions at the time

   • How transmembrane ionic interactions structurally stabilize RNF170 not visualized
   • Link between impaired Ca2+ mobilization and neuronal degeneration not established
3. 2015 Medium

   Demonstrated in vivo that loss of Rnf170 elevates IP3 receptor levels in a tissue-restricted manner and produces a neurological phenotype, validating the degradation function in the intact organism.

   Evidence Rnf170 knockout mouse with gait/proprioception analysis and Itpr1 Western blot across brain regions

   PMID:26433933

   Open questions at the time

   • Why Itpr1 accumulation is cerebellar/spinal but not cortical is unexplained
   • Cell-autonomous basis of the neuronal phenotype not dissected
4. 2019 High

   Expanded RNF170 substrate scope to innate immunity, showing it degrades TLR3 to restrain antiviral signaling, establishing a role beyond Ca2+ homeostasis.

   Evidence Co-IP, site-mapped K48-linked ubiquitination at K766, and RNF170 knockout with in vitro/in vivo immune response assays

   PMID:31076723

   Open questions at the time

   • Whether ERLIN1/2 recruits RNF170 to TLR3 as it does for IP3 receptors not tested
   • Relationship between immune and neurological functions of RNF170 unknown
5. 2019 Medium

   Confirmed bi-allelic loss-of-function RNF170 mutations cause autosomal recessive HSP through disrupted ERAD-mediated IP3 receptor degradation, cementing the gene-disease link.

   Evidence Patient fibroblast assays, mutant SH-SY5Y cells, and zebrafish gene knockdown

   PMID:31636353

   Open questions at the time

   • Causal chain from IP3 receptor accumulation to motor neuron degeneration not delineated
   • Zebrafish knockdown not complemented by rescue in the same report
6. 2022 Low

   A nonsense variant reducing RNF170 mRNA and protein reinforced loss-of-function as the disease mechanism in HSP.

   Evidence RT-qPCR and Western blot in patient-derived cells

   PMID:36046950

   Open questions at the time

   • Single patient with no new pathway mechanism
   • No functional Ca2+ or substrate readout in this case
7. 2024 Medium

   Defined the structural basis of RNF170 scaffolding, mapping conserved luminal N-terminal regions of RNF170 and TMUB1 onto distinct interfaces of the ERLIN SPFH domain, explaining how disease variants disrupt complex assembly.

   Evidence Co-IP/pulldown, 3D structural modelling, deletion/variant mapping, and omics of ERLIN-knockout HeLa cells

   PMID:38782601

   Open questions at the time

   • No experimental high-resolution structure of the assembled complex
   • Functional role of TMUB1 within the RNF170-ERLIN module not defined
8. 2025 Medium

   Identified DEK as an additional RNF170 substrate, with K48-linked ubiquitination at K349 suppressing RIPK1-PANoptosis, broadening the ligase's cell-death regulatory role.

   Evidence Mass spectrometry, molecular docking, site-mapped ubiquitination, and PANoptosis pathway assays in bronchial epithelial cells

   PMID:40120540

   Open questions at the time

   • RNF170-specific contribution not cleanly separated from RNF149
   • Whether DEK targeting is ERLIN-dependent untested

• How RNF170 selects among its diverse substrates (IP3 receptors, TLR3, DEK) and whether ERLIN1/2 scaffolding operates for all of them remains unresolved.
• No unifying recruitment logic across the three substrate classes
• Tissue-specific substrate preference and its relation to disease phenotype unknown