**1. Introduction**

Ubiquitin (Ub) is a 76-amino-acid protein that is highly conserved among all eukaryotes. Ubiquitylation, which involves the conjugation of ubiquitin to the lysine residues of various cellular proteins, is one of the most prevalent post-translational modifications of proteins, and is usually catalyzed by a three-enzyme cascade consisting of Ub-activating enzymes (E1s), Ub-conjugating enzymes (E2s), and Ub ligases (E3s). In mammals, there are 10 or fewer E1 activating enzymes, dozens of E2 conjugating enzymes, and hundreds of E3 ligases; these enzymes regulate the ubiquitylation of numerous proteins [1]. In ubiquitylation, E1 initially activates ubiquitin by adenylating it at the C-terminal glycine residue in an adenosine triphosphate-dependent process; this activated ubiquitin is then captured by the catalytic cysteine of the E1, forming a thioester intermediate. Then, the thioester ubiquitin is transferred from the enzyme active site of E1 to the catalytic center cysteine residue of E2 via a trans-thioesterification reaction [2]. Finally, E3 mediates the transfer of ubiquitin from E2 to a substrate protein. Both the efficiency and the substrate specificity of the ubiquitylation reaction depend on E3 ligases. Depending on the mechanism by which ubiquitin is transferred from E2 to the substrate, E3 is classified into three broad families: Really Interesting New Gene (RING) finger domain-,

Homologous to E6-associated protein C Terminus (HECT) domain-, or RING Between RING (RBR) domain-containing ubiquitin ligases. While RING E3 ligases, the major family among them, facilitate the direct transfer of ubiquitin from E2–ubiquitin intermediates to the substrate protein [3], HECT and RBR E3 ligases contain an active-site cysteine that forms a thioester with ubiquitin before transferring it to the substrate protein [4,5]. The selective pairing between E2 and the multiple cognate E3s confers the specificity necessary for the regulation by ubiquitylation of various biological pathways.

Ubiquitin is conjugated with a lysine residue of a substrate via its C-terminal carboxyl group and can also attach itself via the N-terminal methionine (M1) and seven lysine residues (K6, K11, K27, K29, K33, K48, and K63). As a result, a substrate protein is modified with a single monoubiquitin, multiple monoubiquitins, or polyubiquitin chain. Such ubiquitin attachments can be reversed in the process of deubiquitylation by deubiquitinase (DUB) [6]. Owing to the reversible nature of this modification, the ubiquitin pool of cells is divided into di fferent fractions, including free monoubiquitins, covalently linked mono- and polyubiquitin–protein complexes, and unanchored polyubiquitin. These di fferent linkage types and lengths a ffect substrate proteins in di fferent biological and biochemical ways and play an essential role in regulating a considerable number of significant cellular functions (e.g., protein degradation, endocytosis of membrane proteins, transcriptional control, DNA repair, and cell cycle regulation) [7]. The principal and abundant forms are K48-linked and K63-linked polyubiquitin chains. K48-linked polyubiquitin functions as a signal of proteasomal degradation, whereas K63-linked polyubiquitin chains have non-degradative roles in cellular signaling, intracellular tra fficking, the DNA damage response, and other contexts [8,9].

In this review, we focus on E3 ligases, *RNF183*, *RNF186*, *RNF182*, and *RNF152*, which are closely related genes encoding a RING-finger domain (C3HC4) at its N-terminus and one or two predicted transmembrane domains at its C-terminus with high homology (Figure 1) [10]. As common features, these E3s are expressed in specific tissues, such as the kidney, nervous system, and colon, and are localized in the lysosome (Table 1) [10]. Hereinafter, these ubiquitin ligases are referred to as the RNF183 family. In this review, we summarize our current understanding of the molecular mechanisms underlying the functions and regulation of these E3s in diseases.

**Figure 1.** RNF183 family: (**a**) The phylogenetic tree for C3H2C3-RING E3s with transmembrane. Protein sequences for E3s were aligned with a multiple sequence alignment using the CLUSTALW (http://www.genome.jp/tools/clustalw); (**b**) The comparison of the domain structures of the RNF183 family. Information on the domain structure of RNF183 family protein was obtained from UniProt (https://www.uniprot.org) for RNF183 (Q96D59), RNF186 (Q9NXI6), RNF182 (Q8N6D2), and RNF152 (Q8N8N0). RING, C3H2C3-RING domain; TM, transmembrane domain; a.a., amino acids.


**Table 1.** Features of RNF183 family.
