**8. Conclusions**

Members of the RNF183 family are widely expressed in the ER, Golgi apparatus, endosomes, and lysosomes. Although their substrates do not overlap with each other, they are involved in some common signaling pathways, such as mTORC1 and NF-κB (Table 1). The tissue expression pattern of these E3s is restricted, but overlaps in some tissues, such as the kidney (RNF183, RNF152, and RNF186), the nervous system (RNF152 and RNF182), and the colon (RNF186 and RNF183) [10]. Thus, it is possible that these E3s could function competitively or cooperatively in the regulation of common pathways. The tissue- and development-specific expression of the RNF183 family suggests that it plays an essential role in specific biological functions. To address the problem of dissociated phenotype in the development of knockout mice [43] and species other than mammals [41,42], it is necessary to establish mice with the knockout of two or more genes. It is also important to investigate whether the RNF183 family works in a coordinated and compensatory manner. On the other hand, it is very difficult to identify the substrates of E3, and experiments involving overexpression alone cannot reveal the true physiological function of a substrate. Therefore, the development of technology for identifying in vivo substrates will be important.

**Author Contributions:** T.O. and M.K. wrote the original draft; K.I. and M.K. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by Grants-in-Aid for Scientific Research (KAKENHI: 19K16373, 18H06105, 18K06685, 17H06416, and 17H01424) from the Japan Society for the Promotion of Science, Japan.

**Conflicts of Interest:** The authors declare no conflict of interest.
