RNF149 is a RING finger E3 ubiquitin ligase that functions as a regulatory protein controlling protein degradation across multiple physiological contexts 1. As an E3 ligase, RNF149 catalyzes ubiquitin-dependent proteasomal degradation of diverse substrates, including BRAF 1, IFNGR1 2, IRF3 3, PHLPP2 4, and DEK 5. Mechanistically, RNF149 promotes K27, K33, and K48-linked ubiquitination at specific residues on target proteins, directing them toward proteasomal degradation 35. In cardiac macrophages following myocardial infarction, RNF149 restricts excessive inflammation by degrading IFNGR1, thereby limiting type-II interferon signaling and promoting cardiac repair 2. During viral infection, RNF149 negatively regulates antiviral responses by degrading IRF3, reducing interferon-β production 3. Clinically, RNF149 dysregulation contributes to disease pathogenesis across multiple conditions. Elevated RNF149 expression confers cisplatin resistance in esophageal squamous cell carcinoma by destabilizing PHLPP2 and activating PI3K/AKT signaling 4. Conversely, reducing RNF149 levels restores tau proteostasis in tauopathy models, suggesting therapeutic potential for Alzheimer's disease 6. RNF149 modulation also regulates asthma pathogenesis through DEK degradation and PANoptosis inhibition 5, and serves as a therapeutic target for ROR1-positive cancers via PROTAC technology 7.