RNF170

RNF170 is an endoplasmic reticulum membrane-anchored RING-domain E3 ubiquitin ligase that controls the turnover of inositol 1,4,5-trisphosphate receptors (IP3Rs) and additional substrates through proteasomal degradation. RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) scaffold complex, which recruits it to activated IP3Rs; RNF170 then catalyzes monoubiquitination and K48- and K63-linked polyubiquitination of IP3Rs, driving their proteasomal destruction and thereby shaping intracellular Ca²⁺ signaling (PMID:21610068, PMID:25882839). Beyond IP3R, RNF170 ubiquitinates TLR3 (K48-linked at K766) to promote its degradation and restrain TLR3-triggered innate immune signaling (PMID:31076723), and mediates K48-linked polyubiquitination of the chromatin protein DEK at K349 (PMID:40120540). Loss-of-function mutations in RNF170 cause autosomal dominant sensory ataxia (ADSA) and autosomal recessive hereditary spastic paraplegia, linked to impaired IP3R degradation and defective Ca²⁺ homeostasis in the cerebellum and spinal cord (PMID:25882839, PMID:26433933, PMID:31636353).

1. 2011 High

   Identification of RNF170 as the E3 ligase responsible for activated IP3R ubiquitination resolved the long-standing question of which enzyme marks IP3Rs for proteasomal degradation, and established that the erlin1/2 complex acts upstream to recruit RNF170 to its substrate.

   Evidence RNAi, dominant-negative overexpression, co-immunoprecipitation, and subcellular fractionation in mammalian cells

   PMID:21610068

   Open questions at the time

   • The ubiquitin chain types deposited by RNF170 on IP3R were not resolved
   • In vivo physiological consequences of RNF170 loss were unknown
   • The structural basis of the erlin1/2–RNF170 interaction was undefined
2. 2015 High

   Characterization of the ADSA-causing R199C mutation and CRISPR knockout revealed that RNF170 is responsible for all ubiquitin conjugate types on activated IP3Rs (mono, K48, K63), that ionic interactions within its transmembrane domains stabilize the protein, and that loss of RNF170 impairs IP3R-mediated Ca²⁺ mobilization in patient cells — directly linking the enzyme to a human neurodegenerative disease mechanism.

   Evidence Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca²⁺ imaging in ADSA patient lymphoblasts, proteasome inhibitor chase

   PMID:25882839

   Open questions at the time

   • Whether IP3R accumulation alone is sufficient to cause neurodegeneration was not tested
   • The E2 ubiquitin-conjugating enzyme partnering with RNF170 was not identified
3. 2015 Medium

   An Rnf170 knockout mouse demonstrated region-specific accumulation of Itpr1 in cerebellum and spinal cord (but not cortex), establishing that RNF170 controls IP3R turnover in vivo in the precise neural territories affected in sensory ataxia.

   Evidence Rnf170 knockout mouse, immunoblot of regional brain lysates, gait behavioral analysis

   PMID:26433933

   Open questions at the time

   • The basis for tissue-specific IP3R accumulation (e.g., differential erlin expression) was not determined
   • Electrophysiological or circuit-level consequences in cerebellum were not examined
4. 2019 High

   Discovery that RNF170 ubiquitinates TLR3 at K766 via K48-linked chains to promote its proteasomal degradation broadened RNF170's substrate repertoire beyond IP3Rs and established it as a negative regulator of TLR3-mediated innate immunity.

   Evidence Reciprocal co-immunoprecipitation in macrophages, K766 site mutagenesis, RNF170 KO cells and mice with immune signaling readouts

   PMID:31076723

   Open questions at the time

   • Whether erlin1/2 scaffolds are required for TLR3 ubiquitination by RNF170 was not addressed
   • Physiological immune phenotypes (infection susceptibility) in RNF170 KO mice were not characterized
5. 2019 Medium

   Identification of autosomal recessive loss-of-function RNF170 mutations causing hereditary spastic paraplegia, confirmed by impaired IP3R degradation in patient fibroblasts and phenocopy in zebrafish, established that RNF170 deficiency underlies distinct upper and lower motor neuron disease depending on allelic severity.

   Evidence Patient exome sequencing, fibroblast IP3R degradation assays, zebrafish morpholino knockdown

   PMID:31636353

   Open questions at the time

   • The precise threshold of residual RNF170 activity that distinguishes ADSA from HSP is unknown
   • Rescue experiments restoring RNF170 in patient cells were not reported
6. 2024 Medium

   Mapping of the luminal N-terminal motif in RNF170 (and TMUB1) that binds the SPFH domain of erlin subunits provided the first structural model for how ER membrane E3 ligases are organized within erlin-scaffolded nanodomains, and linked this complex to cholesterol esterification and Golgi morphology.

   Evidence Co-immunoprecipitation, domain mutagenesis, 3D structural modelling, erlin1/2 double-KO HeLa phenotyping

   PMID:38782601

   Open questions at the time

   • An experimental high-resolution structure of the erlin–RNF170 interface is lacking
   • Whether cholesterol-related phenotypes depend specifically on RNF170 catalytic activity was not tested
7. 2025 Medium

   Identification of DEK as a third RNF170 substrate (K48-linked ubiquitination at K349) extended the enzyme's known substrate repertoire to a nuclear chromatin factor, indicating RNF170 functions are not restricted to ER-resident proteins.

   Evidence Mass spectrometry, molecular docking, co-immunoprecipitation and ubiquitination site mutagenesis in bronchial epithelial cells

   PMID:40120540

   Open questions at the time

   • DEK is a nuclear protein; the compartment in which RNF170 encounters DEK is unclear
   • Physiological consequence of DEK degradation by RNF170 beyond bronchial epithelial cells is unknown
   • Whether RNF170 or RNF149 is the primary E3 for DEK was not delineated

• The cognate E2 enzyme(s) for RNF170, the full structural basis of the erlin–RNF170 complex, and the mechanism by which RNF170 selects among its diverse substrates remain unresolved.
• No E2 conjugating enzyme has been identified for RNF170
• No high-resolution structure of the erlin1/2–RNF170 complex exists
• The substrate selectivity mechanism across IP3R, TLR3, and DEK is unknown