**4. RNF182**

RNF182 is the member of the RNF183 family on which the fewest reports have been published. It was initially identified as an upregulated gene in postmortem brains of patients with Alzheimer's disease (AD) [35]. RNF182 is selectively expressed in the nervous system, such as the cortex, hippocampus, cerebellum, and spinal cord, but not in the heart, liver, kidney, and skeletal muscle. RNF182 is expressed in differentiated Ntera2 (NT2) neurons and was shown to be upregulated by oxygen and glucose deprivation. RNF182 overexpression can initiate the death of neuronal cells. In addition, yeas<sup>t</sup> two-hybrid screening revealed that V-type proton ATPase 16 kDa proteolipid subunit (ATP6V0C) is a substrate of RNF182. RNF182 promotes the degradation of ATP6V0C via the proteasome pathway. Because ATP6V0C is a key component of gap junctions and neurotransmitter release channels, the upregulation of RNF182 in AD brains might induce ATP6V0C degradation and contribute to the pathophysiology of AD.

Next, RNF182 was identified as a gene associated with Rett syndrome. Patients with Rett syndrome often exhibit heterozygous mutations in the methyl-CpG-binding protein 2 (MECP2) gene encoding a transcriptional modulator [63]. Gene expression profiles obtained by microarray analysis revealed that RNF182 is upregulated in mutant MeCP2 fibroblasts obtained from patients with Rett syndrome [36]. Since, as described above [35], RNF182 possibly compromises brain function, it is speculated to be involved in postnatal neurodevelopmental abnormalities associated with Rett syndrome.

Although RNF182 appears to be specifically expressed in the nervous system, its expression and function in other tissues were reported. Rnf182 was also shown to be upregulated in a rat model of myocardial ischemia–reperfusion injury (MIRI) [37]. Its silencing by shRNA was shown to reduce myocardial infarct size and myocardial cell apoptosis in this rat model. Intriguingly, RNF182, as well as RNF152 [43,44] and RNF186 [24], is associated with the mTOR signaling pathway, since Rnf182 silencing and treatment with phosphoesterase, an inhibitor of the mTOR signaling pathway, reverse the effect of Rnf182 silencing in the MIRI rat. Thus, it is likely that Rnf182 silencing activates the mTOR signaling pathway, resulting in improved ventricular remodeling after MIRI. However, the target substrate of RNF182 was not identified in this study.

The expression of RNF182 has been observed in immune tissues such as lymph nodes and spleen and in immune cells such as macrophages and dendritic cells [38], although the levels of expression were not compared with that in nerve tissues. Lipopolysaccharide, poly(I:C) and CpG, which is involved in Toll-like receptor (TLR) signaling, induced RNF182 expression. Moreover, RNF182 silencing can specifically suppress TLR-induced activation of NF-κB and the NF-κB-mediated production of proinflammatory cytokines. RNF182 mediates K48-linked polyubiquitylation of the subunit p65 of NF-κB and its degradation via the proteasome pathway in macrophages. Therefore, RNF182 may be upregulated by immune responses and involved in the feedback of inflammatory responses.
