PDZRN3 (PDZ domain containing ring finger 3) is an E3 ubiquitin-protein ligase that functions as a key regulator of protein trafficking and cellular differentiation. The protein contains a RING-finger motif, two PDZ domains, and nuclear localization signals, enabling its role as a ubiquitin ligase 1. PDZRN3 mediates ubiquitination-dependent endocytosis of multiple substrates: it promotes MUSK degradation during myogenic differentiation 2, regulates CLDN16 localization in renal tubules to control Mg2+ reabsorption 3, and modulates SMCT1 transporter function by competing with PDZK1 4. PDZRN3 is regulated by Wnt5a-Ror signaling through phosphorylation-dependent proteasomal degradation, which is essential for cell migration 5. Notably, PDZRN3 expression is high during heart development but decreases postnatally; overexpression causes eccentric hypertrophic cardiomyopathy and heart failure, while knockout protects against pressure-overload-induced dysfunction 6. Additionally, HPV-16 and HPV-18 E6 proteins target PDZRN3 for proteasomal degradation via its PDZ binding motif, linking viral infection to disrupted STAT signaling 7. These findings establish PDZRN3 as a multifunctional ubiquitin ligase critical for tissue homeostasis, differentiation, and ion balance with potential implications in viral pathogenesis and cardiac disease.