Abstract
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.
Highlights
Protein post-translational modification (PTM) refers to a modification of a polypeptide chain that occurs after its biosynthesis
This study suggests that reducing the activation of the inositol-requiring enzyme 1α (IRE1α)-TNF receptor-associated factor 2 (TRAF2)-Apoptosis signal-regulating kinase 1 (ASK1)-Jun N-terminal kinase (JNK) pathway by silencing Ring Finger Protein 13 (RNF13) might be beneficial to alleviate some of the motor dysfunction and to prevent the dopaminergic neuron damage in a Parkinson’s disease mouse model [73]
While we don’t yet know the exact molecular mechanism involved and how it is linked to the increased apoptosis markers described by Edvardson et al, our results suggest that RNF13 L311S and L312P disrupt the endolysosomal pathway due to the loss of interaction with the adaptor protein (AP)-3 complex [59,74]
Summary
Protein post-translational modification (PTM) refers to a modification of a polypeptide chain that occurs after its biosynthesis. A RING-type E3 does not possess an active cysteine in its functional RING domain and, mediates the transfer of Ub to the substrate protein from the Ub-charged. RBR-type E3s are considered to be a hybrid of the HECT and RING domains since these enzymes function by using an E2-binding RING structure and a second RING domain that contains an active cysteine for the formation of an intermediate E3~Ub conjugate before the transfer of Ub to a substrate [6,23]. The PA domain is a conserved sequence of about 120 amino acids implicated in protein-protein interactions [27,29] It was initially identified in non-catalytic regions of plant vacuolar sorting receptors and zinc-containing metalloproteases, but the exact role of this domain in the PA-TM-RING family of Ub ligases remains unclear [27,30]. The use of the Godzilla Ub ligasedead mutant (DN for dominant-negative) did not result in enlarged endosomes, implying that Godzilla’s impact on endosomal maturation is through RING-dependent substrate ubiquitination [33]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
