| Biological context/pathway | RNF5 molecular action | Key substrates/partners and specific lysines/linkages when available | Subcellular localization context | Recent 2023–2024 findings/applications with quantitative details | Primary supporting source |
|---|---|---|---|---|---|
| ERAD / proteostasis | RING E3 ubiquitin ligase; ubiquitinates immature membrane proteins for proteasomal ERAD | CFTR N-terminus/MSD1 recognized; partners include UBE2J1, UBE2D3, RNF185, gp78/AMFR, HERC3; acts mainly on immature CFTR Band B (pqac-00000009, pqac-00000013, pqac-00000014, pqac-00000016) | ER-anchored / ER-embedded membrane ligase with C-terminal TM region(s) (pqac-00000009, pqac-00000011, pqac-00000016) | Genome-wide CRISPR screen assayed **20,528 genes** and found **207 high-confidence hits (FDR <1%)**; RNF5 was top E3 hit, UBE2D3 top E2; RNF5 KO had only modest effect, supporting pathway redundancy (pqac-00000013, pqac-00000021) | *Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states* (2024), https://doi.org/10.1091/mbc.e23-08-0336 |
| CFTR-F508del | Promotes ubiquitination and degradation of misfolded F508del-CFTR; early triage E3 in sequential ERQC | F508del-CFTR; sequential action with CHIP; RNF185 can compensate; correctors stabilize RNF5-resistant folding states (pqac-00000009, pqac-00000013, pqac-00000014, pqac-00000017) | ER membrane / ERQC on nascent or immature CFTR before plasma-membrane maturation (pqac-00000009, pqac-00000013, pqac-00000016, pqac-00000017) | F508del occurs in **>80%** of people with CF / affects **~80%** of CF patients worldwide; RNF5 suppression improved intestinal malabsorption and CFTR activity in F508del-transgenic mice; no RNF5-targeting compounds reported in clinical trials in the provided context (pqac-00000009, pqac-00000020, pqac-00000022, pqac-00000024) | *Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?* (2024), https://doi.org/10.1007/s00018-024-05295-z |
| CFTR-F508del therapeutic targeting | Pharmacologic RNF5 inhibition / degradation to reduce CFTR ubiquitination | inh-2 (first-in-class RNF5 inhibitor), analogue 16, FX12; analogue 16 effect lost with RNF5 siRNA, supporting on-target action (pqac-00000010, pqac-00000012, pqac-00000015) | ER-associated RNF5 targeted indirectly by small molecules in airway epithelial cell models (pqac-00000010, pqac-00000012) | Compound testing commonly at **5 μM**; VX-809 **1–3 μM**, VX-445 **3 μM**, VX-661 + VX-445 **10 μM + 3 μM**, MG-132 **10 μM**; analogue 16 was among the most promising compounds (11, 16, 21) and improved rescue with ELX/TEZ/IVA in CFBE41o− cells; FX12 active in BHK cells but not differentiated primary airway epithelia (pqac-00000010, pqac-00000012, pqac-00000018, pqac-00000022) | *Innovative Strategy toward Mutant CFTR Rescue in Cystic Fibrosis: Design and Synthesis of Thiadiazole Inhibitors of the E3 Ligase RNF5* (2023), https://doi.org/10.1021/acs.jmedchem.3c00608 |
| Innate immunity: cGAS-STING / MAVS / IRF3 | E3 ligase that mainly promotes degradative ubiquitination of antiviral signaling adaptors; K48 linked for STING/MAVS in mammalian studies summarized in review | STING/MITA at **K150** (K48-linked); MAVS/VISA at **K362** and **K461**; activated IRF3 degraded after recruitment by JMJD6; viral proteins can hijack RNF5 and alter linkage usage (K27/K29/K63 also discussed in viral contexts) (pqac-00000004, pqac-00000005, pqac-00000007) | ER-associated; MAVS regulation occurs in mitochondria-associated antiviral signaling context; STING at ER/ERGIC-associated innate immune membranes (pqac-00000005, pqac-00000007) | 2024 review emphasizes RNF5 as a negative regulator of antiviral innate immunity and a possible host-directed target; no clinical-stage RNF5 immune modulators reported in the provided context (pqac-00000002, pqac-00000005, pqac-00000007) | *RNF5: inhibiting antiviral immunity and shaping virus life cycle* (2024), https://doi.org/10.3389/fimmu.2023.1324516 |
| Autophagy | Regulates autophagy by targeting autophagy machinery components for degradation | ATG4B is a reported RNF5 substrate; inh-2 and analogue 16 increase basal autophagy consistent with blocking RNF5-mediated turnover; PTGDR2 can compete with ATG4B for RNF5 binding in gastric CSC context (pqac-00000010, pqac-00000011, pqac-00000012) | ER-associated RNF5 with effects on cytosolic autophagy regulators (pqac-00000011, pqac-00000012) | Autophagy vacuoles increased with inh-2 and compounds 11/16/21; torin-1 used at **20 nM**, SAR-405 at **2 μM** in functional autophagy assays (pqac-00000010, pqac-00000018) | *Innovative Strategy toward Mutant CFTR Rescue in Cystic Fibrosis: Design and Synthesis of Thiadiazole Inhibitors of the E3 Ligase RNF5* (2023), https://doi.org/10.1021/acs.jmedchem.3c00608 |
| Cardiovascular | Protective E3-ligase-associated role in stress signaling; inhibits ASK1 pathway in MI model | ASK1 pathway implicated; whether direct ubiquitination of ASK1 is established was unresolved in provided context (pqac-00000004) | Cardiac cells/tissue; RNF5 downregulated in infarcted mouse heart and OGD-treated cardiomyocytes (pqac-00000004) | 2024 mouse/cell study: RNF5 knockout worsened myocardial infarction-associated dysfunction, inflammation, and apoptosis, while overexpression was protective; quantitative effect sizes not provided in context (pqac-00000004) | *RING finger protein 5 protects against acute myocardial infarction by inhibiting ASK1* (2024), https://doi.org/10.1186/s12872-024-04070-z |
| Oncology / other | Context-dependent E3 ligase affecting tumor signaling, proteostasis, and therapeutic response | EphA2/Eph receptors, paxillin, ATG4B; Open Targets links RNF5 to neoplasm, glioblastoma, ALL, cystic fibrosis, and EAE based on supporting literature (pqac-00000003, pqac-00000005, pqac-00000000) | ER-associated ligase with downstream effects on signaling, migration, and transcriptional programs (pqac-00000003, pqac-00000005) | Open Targets evidence scores in provided context: cystic fibrosis association **0.4753**, neoplasm **0.1277**, glioblastoma **0.1098**, ALL **0.1049**, EAE **0.1039**; preclinical therapeutic interest noted in AML, KSHV/PEL, and breast-cancer signaling, but no clinical trials reported here (pqac-00000000, pqac-00000005) | Open Targets disease-target associations for RNF5 (accessed via provided context) (pqac-00000000) |


*Table: This table summarizes evidence-based functional annotation for human RNF5 (UniProt Q99942), organized by pathway context, molecular action, substrates, localization, and recent translational findings. It is useful as a compact reference for RNF5’s validated roles in ERAD, CFTR quality control, innate immunity, autophagy, cardiovascular biology, and disease associations.*