E3 ubiquitin-protein ligase RNF216 (RNF216)

E3 ubiquitin-protein ligase RNF216 (RNF216) is an enzyme that mediates the transfer of ubiquitin from E2 ubiquitin-conjugating enzymes to specific substrate proteins, leading to their modification and subsequent degradation by the proteasome[1][6][7]. RNF216 is a cytoplasmic, multi-domain protein with RING finger and zinc finger motifs, necessary for its protein-protein interactions and enzymatic activity[1][2][5]. It predominantly assembles K63-linked ubiquitin chains, a process essential for regulating innate immune signaling pathways (notably control of NF-κB activation), synaptic plasticity, and neurodevelopment[2][3][4][5]. RNF216 plays roles in inflammation, autophagy, and the nervous system where it controls trafficking of key neuronal receptors by ubiquitinating substrates such as Arc[4]. Mutations in RNF216 cause Gordon Holmes syndrome, a rare disorder characterized by neurodegeneration (cerebellar ataxia, dementia) and endocrine dysfunction (hypogonadotropic hypogonadism)[3][5]. Its enzyme activity and substrate specificity are regulated by protein interactions and phosphorylation. No direct drug modulators are currently in clinical use or advanced development.

Other names

TRIAD3UBCE7IP1ZINRING finger protein 216RING-type E3 ubiquitin transferase RNF216Triad domain-containing protein 3Ubiquitin-conjugating enzyme 7-interacting protein 1Zinc finger protein inhibiting NF-kappa-BCAHHU7I1

Drugs would modulate ubiquitin ligase activity (e.g., inhibit or enhance tagging of substrate proteins via K63-linked or K48-linked ubiquitin chain formation)