Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence^1,2. We previously found that either deficiency or inhibition of protein-tyrosine phosphatase (PTP1B) promotes human epidermal growth factor receptor 2-positive breast cancer cell death in hypoxia by activation of RNF213 (ref. ³), a large protein with multiple AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) implicated in Moyamoya disease, lipotoxicity and innate immunity⁴. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 tyrosine phosphorylation and, consequently, its oligomerization and RZ domain activation. The RZ domain ubiquitylates and induces the degradation of the major NF-κB regulator CYLD/SPATA2. Decreased CYLD/SPATA2 levels lead to NF-κB activation and induction of the NLRP3 inflammasome which, together with hypoxia-induced endoplasmic reticulum stress, triggers pyroptotic cell death. Consistent with this model, CYLD deletion phenocopies, whereas NLRP3 deletion blocks, the effects of PTP1B deficiency on human epidermal growth factor receptor 2-positive breast cancer xenograft growth. Reconstitution studies with RNF213 mutants confirm that the RZ domain mediates tumour cell death. In concert, our results identify a unique, potentially targetable PTP1B–RNF213–CYLD–SPATA2 pathway critical for the control of inflammatory cell death in hypoxic tumours, provide new insights into RNF213 regulation and have potential implications for the pathogenesis of Moyamoya disease, inflammatory disorders and autoimmune disease.

缺氧癌细胞对许多抗肿瘤疗法产生抵抗力，并且可以播种复发^1,2。我们之前发现，蛋白质酪氨酸磷酸酶 （PTP1B） 的缺乏或抑制通过激活 RNF213（参考文献 ³）促进人表皮生长因子受体 2 阳性乳腺癌细胞在缺氧中死亡，RNF213 是一种具有多个 AAA-ATP 酶结构域和两个泛素连接酶结构域（RING 和 RZ）的大蛋白，与烟雾病、脂毒性和先天免疫有关4.在这里，我们报道了 PTP1B 和 ABL1/2 相互控制 RNF213 酪氨酸磷酸化，从而控制其寡聚化和 RZ 结构域激活。RZ 结构域泛素化并诱导主要 NF-κB 调节因子 CYLD/SPATA2 的降解。CYLD/SPATA2 水平降低导致 NF-κB 激活和诱导 NLRP3 炎性小体，这与缺氧诱导的内质网应激一起触发焦亡细胞死亡。与该模型一致，CYLD 缺失表型拷贝，而 NLRP3 缺失阻断，PTP1B 缺陷对人表皮生长因子受体 2 阳性乳腺癌异种移植生长的影响。RNF213 突变体的重建研究证实 RZ 结构域介导肿瘤细胞死亡。总之，我们的结果确定了一种独特的、可能具有靶向性的 PTP1B-RNF213-CYLD-SPATA2 通路，对控制缺氧性肿瘤中的炎症细胞死亡至关重要，为 RNF213 调节提供了新的见解，并对烟雾病、炎症性疾病和自身免疫性疾病的发病机制具有潜在意义。