The ubiquitin-proteasome system is of fundamental importance in all fields of biology due to its impact on proteostasis and in regulating cellular processes. Ubiquitination, a type of protein post-translational modification, involves complex enzymatic machinery, such as E3 ubiquitin ligases. The E3 ligases regulate the covalent attachment of ubiquitin to a target protein and are involved in various cellular mechanisms, including the cell cycle, cell division, endoplasmic reticulum stress, and neurotransmission. Because the E3 ligases regulate so many physiological events, they are also associated with pathologic conditions, such as cancer, neurological disorders, and immune-related diseases. This review focuses specifically on the protease-associated transmembrane-containing the Really Interesting New Gene (RING) subset of E3 ligases. We describe the structure, partners, and physiological functions of the Drosophila Godzilla E3 ligase and its human homologues, RNF13, RNF167, and ZNRF4. Also, we summarize the information that has emerged during the last decade regarding the association of these E3 ligases with pathophysiological conditions, such as cancer, asthma, and rare genetic disorders. We conclude by highlighting the limitations of the current knowledge and pinpointing the unresolved questions relevant to RNF13, RNF167, and ZNRF4 ubiquitin ligases.
Keywords: E3 ligase; Godzilla; PA-TM-RING family; RNF13; RNF167; ZNRF4; pathological dysfunction; ubiquitin.