| Category | Summary |
|---|---|
| Identity/domains | - Human **RNF170** corresponds to UniProt **Q96K19**, a **RING-type E3 ubiquitin ligase** studied as an ER-membrane regulator of protein turnover and signaling.<br>- Foundational work defines RNF170 as a **257 aa RING-HC protein** with catalytic dependence on **Cys101/His103**; this matches the UniProt RING-domain annotation and ER-associated function. (pqac-00000005, pqac-00000007) |
| Localization/topology | - RNF170 is an **integral endoplasmic reticulum (ER) membrane** protein.<br>- Topology predictions and biochemical fractionation place its **N-terminus in the ER lumen** and its **RING domain/C-terminus in the cytosol**, positioning the catalytic machinery to ubiquitinate cytosolic receptor lysines.<br>- RNF170 localizes in **ERLIN-positive cholesterol-rich ER nanodomains**. (pqac-00000005, pqac-00000007, pqac-00000012) |
| Core enzymatic activity | - RNF170 catalyzes **E3 ubiquitin transfer** in vitro using **UBE1 + UbcH5b** and ubiquitin, generating a high-molecular-weight ubiquitin smear typical of ligase activity.<br>- Catalysis is lost with **RING mutant C101S/H103A**, confirming dependence on the RING domain.<br>- Functionally, RNF170 promotes **proteasome-directed ER-associated degradation (ERAD)** of selected membrane/signaling proteins. (pqac-00000005, pqac-00000007, pqac-00000013) |
| Key substrates | - Best-supported human substrate class: **activated IP3 receptors (IP3Rs)**, especially **IP3R1/IP3R3**, which undergo RNF170-dependent ubiquitination and degradation after stimulation.<br>- In murine innate immunity studies, RNF170 also targets **TLR3**, catalyzing **K48-linked polyubiquitination** at **K766** to drive proteasomal degradation.<br>- TLR3 regulation is strongly supported experimentally, but species context should be noted because the primary paper is in **murine cells/mice**. (pqac-00000000, pqac-00000005, pqac-00000013, pqac-00000015, pqac-00000016) |
| Key interactors/complex | - RNF170 is constitutively associated with the **ERLIN1/2 complex**, which recruits it to activated IP3Rs.<br>- It is also found in complexes containing **p97/VCP-associated ERAD machinery** and, in 2024 work, **TMUB1-L** bridged by ERLIN scaffolds.<br>- Proteomics and co-IP studies repeatedly enrich **ERLIN1, ERLIN2, ITPR3, TMUB1, TMEM259** with RNF170-centered complexes. (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000009, pqac-00000012) |
| Pathways | - RNF170 acts in **ERAD/proteostasis**, especially stimulus-coupled degradation of activated **IP3Rs**.<br>- Through IP3R turnover, RNF170 regulates **ER Ca2+ release signaling** and is therefore connected to neurodegeneration-relevant calcium homeostasis pathways.<br>- Separate immune work places RNF170 in **TLR3 innate immune signaling** as a negative regulator limiting IRF3/NF-kB/STAT1 outputs by degrading TLR3. (pqac-00000000, pqac-00000006, pqac-00000013, pqac-00000026) |
| Disease associations | - **Biallelic loss-of-function RNF170 variants** cause **autosomal recessive hereditary spastic paraplegia (HSP)**, with Open Targets evidence mapped to hereditary/complex HSP.<br>- Earlier literature also linked a **dominant sensory ataxia** phenotype to RNF170 mutation, and mouse knockout models show age-dependent gait abnormalities.<br>- Expert 2024 synthesis places RNF170 within an **ER homeostasis/quality-control disease module** shared across HSP, ataxia, and related neurodegenerative disorders. (pqac-00000000, pqac-00000002, pqac-00000008, pqac-00000026) |
| Recent 2024 developments | - **Veronese et al. 2024** propose that **ERLIN1/2 ring-like scaffolds** bind a conserved luminal motif in **RNF170 and TMUB1-L**, organizing them in cholesterol-rich ER nanodomains.<br>- This work expands RNF170 biology beyond IP3R degradation by linking the ERLIN–RNF170 module to **cholesterol esterification control, Golgi morphology, and secretory pathway regulation**.<br>- 2024 disease reviews and genetics papers further emphasize the **ERLIN1/2–RNF170–IP3R** axis as a recurrent neurogenetic mechanism in spastic paraplegia/ataxia. (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000020, pqac-00000026) |
| Quantitative data points | - **RNF170 knockdown** reduced agonist-induced **IP3R1 polyubiquitination to 57 ± 7% of control**, inhibited IP3R1 down-regulation by roughly **~50%**, and increased basal IP3R1 by **~27 ± 11%**. (pqac-00000005)<br>- In RNF170-deficient models, **IP3R3** rose by about **~4-fold** in patient fibroblasts and **IP3R1** by **~1.8-fold** in RNF170-knockout SH-SY5Y cells. (pqac-00000021)<br>- 2024 ERLIN-loss proteomics/lipidomics reported **SOAT1 log2FC = 0.40, q = 0.07** and phenotyping with **N = 3** biological replicates, including **≥130 cells** for lipid-droplet size and **≥340 cells** for Golgi fragmentation. (pqac-00000009, pqac-00000011) |


*Table: This table condenses the key verified facts about human RNF170 (UniProt Q96K19), including its identity, ER localization, E3 ligase function, substrates, complexes, disease relevance, and notable 2024 advances. It is useful as a quick-reference annotation scaffold anchored to specific evidence contexts.*