Novel Multifaceted Roles for RNF213 Protein

Abstract

Ring Finger Protein 213 (RNF213), also known as Mysterin, is the major susceptibility factor for Moyamoya Arteriopathy (MA), a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Although several rare RNF213 polymorphisms have been reported, no major susceptibility variant has been identified to date in Caucasian patients, thus frustrating the attempts to identify putative therapeutic targets for MA treatment. For these reasons, the investigation of novel biochemical functions, substrates and unknown partners of RNF213 will help to unravel the pathogenic mechanisms of MA and will facilitate variant interpretations in a diagnostic context in the future. The aim of the present review is to discuss novel perspectives regarding emerging RNF213 roles in light of recent literature updates and dissect their relevance for understanding MA and for the design of future research studies. Since its identification, RNF213 involvement in angiogenesis and vasculogenesis has strengthened, together with its role in inflammatory signals and proliferation pathways. Most recent studies have been increasingly focused on its relevance in antimicrobial activity and lipid metabolism, highlighting new intriguing perspectives. The last area could suggest the main role of RNF213 in the proteasome pathway, thus reinforcing the hypotheses already previously formulated that depict the protein as an important regulator of the stability of client proteins involved in angiogenesis. We believe that the novel evidence reviewed here may contribute to untangling the complex and still obscure pathogenesis of MA that is reflected in the lack of therapies able to slow down or halt disease progression and severity.

European Stroke Organisation (ESO) Guidelines on Moyamoya angiopathy Endorsed by Vascular European Reference Network (VASCERN)

“…9,10,19 The role of genetic factors is supported by several elements including the association of MMA with heritable disorders, the high familial rate in East Asia and the geographical distribution of the disease. 19–21 Particularly, a variant of the RNF213 gene, p.R4810K with a strong founder effect was found in East-Asians with MMA but not in Western patients whereas the role of other RNF213 gene variants 20,22 has apparently less association with the disease. 23–30 The diagnosis of MMA is confirmed according to established angiographic diagnostic criteria, 31,32 requiring the presence of a bilateral stenosis or occlusion at the terminal portion of the ICAs and/or at the proximal portion of the anterior and/or the middle cerebral arteries and the development of a network of fragile collateral vessels in the vicinity of the occlusive or stenotic lesions.…”

Increase of Circulating Endothelial Progenitor Cells and Released Angiogenic Factors in Children with Moyamoya Arteriopathy

“…The pathogenesis and etiology of MMA are still unknown, even if the association with genetic disorders, the high familial rate, and the strong linkage with variants of the Ring Finger Protein 213 (RNF213 )/ Mysterin coding gene in East Asian patients strengthen the role of genetic factors in MMA pathogenesis [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Furthermore, several reports have implicated RNF213 as a sensor for mitochondrial dysfunction, hypoxia, and inflammation, and most recently, it has been involved in antimicrobial activity and lipid metabolism [ 16 , 18 , 19 , 20 , 21 ]. The emerging and considerable role of genetic background, although not yet outlined, is sustained by a wide number of pediatric cases.…”

As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

“…Among these rapid responders, E3 ubiquitin ligases represent important lipid-responsive homeostatic regulators of lipid metabolic pathways. [9,[15][16][17][18] E3 ubiquitin ligases regulate cellular signalling, endocytosis and protein degradation, [19,20] and ubiquitination controls the cellular proteome and provides an essential post-translational pathway to regulate protein abundance and stability. [19] E3 ubiquitin ligases covalently transfer ubiquitin to their target proteins.…”

“…Among these rapid responders, E3 ubiquitin ligases represent important lipid‐responsive homeostatic regulators of lipid metabolic pathways. [ 9,15–18 ]…”