Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Abstract

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.