Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation

Abstract

Growing evidence suggest the association between Moyamoya disease (MMD) and immune systems, such as antigen presenting cells in particular. Rnf213 gene, a susceptibility gene for MMD, is highly expressed in immune tissues, however, its function remains unclear. In addition, the physiological role of RNF213 gene polymorphism c.14576G > A (rs112735431), susceptibility variant for MMD, is also poorly understood. By studying Rnf213-knockout (Rnf213-KO) mice with deletion of largest exon32 and Rnf213-knockin (Rnf213-KI) mice with insertion of singlenucleotide polymorphism corresponding to c.14576G > A mutation in MMD patients, we aimed to investigate the role of RNF213 in dendritic cell development, and antigen processing and presentation. First, we found a high level of Rnf213 gene expression in conventional DCs and monocytes. Second, flow cytometric and confocal microscopic analysis revealed ovalbumin protein-pulsed Rnf213-KO and Rnf213-KI DCs showed impaired antigen uptake, proteolysis and reduced numbers of endosomes and lysosomes, and thereby failed to activate and proliferate antigenspecific T cells efficiently. In addition, Rnf213-KI DCs showed a similar phenotype to that of Rnf213-KO BMDCs. In conclusion, our findings suggest the critical role of RNF213 in antigen uptake, processing and presentation.

RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses

“…The main limitation is that we did not test the direct factors contributing to the observed effects. For example, RNF213, as an E3 ubiquitin ligase 7,11,12 , interacts with several proteins to regulate their levels 13 . Downstream of this interaction, changes in RNA binding proteins, transcription factors, or RNA modifying proteins should be responsible for the observed transcriptional and epigenetic changes.…”

“…This stimulates the generation of collateral vessels, which are, in turn, poorly formed due to the effect of RNF213 loss of function inherent in MMD aggravated by yet-to-beidentified immune factors. This model is based on observations made in MMD patients 43,44 , our data, and previously published work 7,13,15 .…”

“…Moreover, the rate of RNF213 mutations in healthy Japanese population ranges between 1.4∼2.7% 6,8 . This, and the association of MMD with autoimmune diseases 9 , led to the hypothesis that RNF213 mutations alone do not cause MMD, but a compendium of environmental and immune factors might be at play 7,10 . Indeed, with the advent of modern technologies that allowed the early diagnosis of MMD in its early stages, understanding the pathophysiologic mechanisms governing its development and progression would allow for potential therapies to be developed or repurposed in order to halt the disease.…”

“…Indeed, with the advent of modern technologies that allowed the early diagnosis of MMD in its early stages, understanding the pathophysiologic mechanisms governing its development and progression would allow for potential therapies to be developed or repurposed in order to halt the disease. Previous research showed that RNF213 regulates immune function and response to bacterial infection 7,11 , involved in regulation of cytoplasmic lipid droplets 12 , regulates vascular development visa non-canonical WNT signaling pathway 13 , regulates neuromuscular development in zebrafish 14 , and regulates inflammatory responses and angiogenesis in endothelial cells 15 .…”

“…MMD is a genetic disease, and polymorphism in the gene RNF213 was identified as a susceptibility gene for its development 6 . RNF213 is an E3 ubiquitin ligase/AAA+ ATPase that belongs to RING (really interesting new gene) finger family 7 . However, the exact mechanism by which RNF213 mutations induce MMD is not known.…”