RNF213-associated urticarial lesions with hypercytokinemia

Louvrier, Camille; Awad, Fawaz; Cosnes, A.; Khouri, Elma El; Assrawi, Eman; Daskalopoulou, Aphrodite; Copin, Bruno; Bocquet, Hélène; Bastaraud, Sandra Chantot; Garcia, Angela Arenas; Moal, F.; Grange, Pierre de la; Duquesnoy, Philippe; Guerrera, Chiara I; Piterboth, William; Ortonne, Nicolas; Chosidow, Olivier; Karabina, Sonia; Amselem, Serge; Giurgea, Irina

doi:10.1016/j.jaci.2022.06.016

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…2b, orange-colored arrows). RNF213/CYLD interaction was recently reported by another group, although its biological significance was not determined 34 . Other top C-Turbo interactors included proteins involved in VEGF signaling, which is induced in hypoxia (FLII, MYOF), inflammation (MAP4K4, SPTLC1), lipotoxicity (SPTLC1, ALDH1B1), and ischemia response (CPEB4), 35,36,37,38,39,40,41 all of which could be potentially relevant for hypoxic cancers.…”

Section: Resultsmentioning

confidence: 96%

Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Bhardwaj,

Antonelli,

Ueberheide

et al. 2023

Preprint

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SummaryHypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ), which is implicated in Moyamoya disease (MMD). Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 levels cause NF-κB activation, which together with hypoxia-induced ER-stress triggers pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain, and RING mutants, including MMD alleles, catalyze LUBAC-independent CYLD/SPATA2 degradation. Our results identify an inflammatory cell death pathway that kills hypoxic tumors, reveal new insights into RNF213 regulation, and have important implications for MMD, atherosclerosis, and inflammatory disorder pathogenesis.

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Section: Resultsmentioning

confidence: 96%

Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Bhardwaj,

Antonelli,

Ueberheide

et al. 2023

Preprint

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“…levels [e.g., IL-1β, tumor necrosis factor alpha (TNFα), IL-6] comparable with an acute cytokine storm. Interestingly, the RNF213 p.(C4177R) mutation was found to reduce the half-life of the RNF213 protein, which correlated with impaired nuclear factor kappa B (NF-κB) activation [31]. This study highlights RNF213 as a clinically relevant mediator of inflammation, a function that might also be important for MMD pathogenesis.…”

Section: Open Accessmentioning

confidence: 83%

Moyamoya disease emerging as an immune-related angiopathy

Asselman

Hemelsoet

Eggermont

et al. 2022

Trends in Molecular Medicine

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“… 40 Recent studies have revealed that dysregulated RNF213 function is associated with autoimmune diseases. 41 , 42 Nevertheless, our study did not explore the potential immunomodulation of RNF213 in angiogenesis. Such research might provide new insights into MMD pathogenesis in future studies.…”

Section: Discussionmentioning

confidence: 97%

RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway

Niu

et al. 2023

Brain

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Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by steno-occlusive changes in the circle of Willis and abnormal vascular network development. Ring finger protein 213 (RNF213) has been identified as an important susceptibility gene for Asian patients, but researchers have not completely elucidated whether RNF213 mutations affect the pathogenesis of MMD. Using donor superficial temporal artery (STA) samples, whole-genome sequencing was performed to identify RNF213 mutation types in MMD patients, and histopathology was performed to compare morphological differences between patients with MMD and intracranial aneurysm (IA). The vascular phenotype of RNF213-deficient mice and zebrafish was explored in vivo, and RNF213 knockdown in human brain microvascular endothelial cells (HBMECs) was employed to analyse cell proliferation, migration, and tube formation abilities in vitro. After bioinformatics analysis of both cell and bulk RNA-seq data, potential signalling pathways were measured in RNF213-knockdown or RNF213-knockout endothelial cells (ECs). We found that MMD patients carried pathogenic mutations of RNF213 that were positively associated with MMD histopathology. RNF213 deletion exacerbated pathological angiogenesis in the cortex and retina. Reduced RNF213 expression led to increased EC proliferation, migration, and tube formation. Endothelial knockdown of RNF213 activated the Hippo pathway effector Yes-associated protein (YAP)/tafazzin (TAZ) and promoted the overexpression of the downstream effector VEGFR2. Additionally, inhibition of YAP/TAZ resulted in altered cellular VEGFR2 distribution due to defects in trafficking from the Golgi apparatus to the plasma membrane and reversed RNF213 knockdown–induced angiogenesis. All these key molecules were validated in ECs isolated from RNF213-deficient animals. Our findings may suggest that loss-of-function of RNF213 mediates the pathogenesis of MMD via the Hippo pathway.

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RNF213-associated urticarial lesions with hypercytokinemia

Cited by 8 publications

References 30 publications

Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Moyamoya disease emerging as an immune-related angiopathy

RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway

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