SPSB3 functions as a substrate-recognition component of a cullin-5-RING E3 ubiquitin-protein ligase complex (CRL5-SPSB3) that mediates proteasomal degradation of target proteins 1. The primary function involves recognizing and binding nucleosome-bound cGAS through a highly conserved C-terminal Asn-Asn (NN) degron motif, catalyzing 'Lys-48'-linked ubiquitination of nuclear cGAS during G1 and G2 phases to maintain low intranuclear cGAS abundance and prevent aberrant immune activation 1. Additionally, SPSB3 targets SNAIL for GSK-3β phosphorylation-dependent ubiquitination and degradation, thereby regulating epithelial-mesenchymal transition (EMT) and cancer metastasis 2. The protein shows tissue-specific expression patterns, being testis-enriched in mice, though Spsb3-knockout mice display normal fertility and spermatogenesis 3. SPSB3 has clinical significance as its expression negatively correlates with SNAIL in esophageal squamous cell carcinoma, with low SPSB3 expression indicating lymph node metastasis and poor survival outcomes 2. The protein has also been identified as a potential biomarker in various diseases including Parkinson's disease and cerebral malaria 45.