E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of multiple substrates including GRIA1, GRIA2, PHOX2A and PHOX2B, STAT1, STAT3 and SIN3B. Independently of its E3 ligase activity, acts as a CTNNB1 stabilizer through USP7-mediated deubiquitination of CTNNB1 promoting Wnt signaling (PubMed:25266658, PubMed:33964137). Plays a critical role in the regulation of nuclear lamina (PubMed:33964137). Modulates synaptic activity and brain functions by promoting degradation of AMPA receptor subunits GRIA1 and GRIA2. The RNF220/ZC4H2 complex monoubiquitinates PHOX2A and PHOX2B to enhance their DNA-binding ability and transactivity (By similarity). Promotes 'Lys-63'-linked polyubiquitination of Gli transcriptional activators and repressors, facilitating their nuclear export by CRM1 to fine-tune the sonic hedgehog/Gli signaling (By similarity). Regulates type I and type II interferon responses upon viral or bacterial infection by mediating 'Lys-63'-linked polyubiquitination of STAT1 (PubMed:32814877). Also regulates STAT3 phosphorylation, nuclear translocation, and transcriptional activity via ubiquitination (PubMed:41219491). Promotes OLIG1 and OLIG2 'Lys-63'-linked polyubiquitination and stabilization, two master regulatory transcription factors involved in oligodendroglial development (PubMed:38324685). {ECO:0000250|UniProtKB:Q6PDX6, ECO:0000269|PubMed:25266658, ECO:0000269|PubMed:32814877, ECO:0000269|PubMed:33964137, ECO:0000269|PubMed:37537194, ECO:0000269|PubMed:38324685, ECO:0000269|PubMed:41219491}. This is the function of Ensembl gene identifier ENSG00000187147 (RNF220, ring finger protein 220).