Abstract
Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence. 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, a large protein with multiple AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) implicated in Moyamoya disease, lipotoxicity and innate immunity. 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.
摘要
低氧状态下的癌细胞会抵抗多种抗肿瘤疗法，并可能导致复发。RNF213是一种具有多个AAA-ATPase结构域和两个泛素连接酶结构域（RING和RZ）的大蛋白，与莫亚莫亚病、脂肪毒性和先天免疫有关。我们在此报告PTP1B和ABL1/2相互控制RNF213的酪氨酸磷酸化，进而控制其寡聚化和 RZ 结构域的激活。RZ结构域泛素化并诱导主要NF-κB调节因子CYLD/SPATA2降解。CYLD/SPATA2水平的降低会导致NF-κB激活并诱导NLRP3炎性体，而NLRP3炎性体与缺氧诱导的内质网应激一起，会引发细胞热解死亡。与这一模型相一致的是，CYLD基因缺失会复制PTP1B基因缺失对人类表皮生长因子受体2阳性乳腺癌异种移植生长的影响，而NLRP3基因缺失则会阻止这种影响。用RNF213突变体进行的重组研究证实，RZ结构域介导了肿瘤细胞的死亡。总之，我们的研究结果确定了一种独特的、可能成为靶点的PTP1B-RNF213-CYLD-SPATA2通路，它对控制缺氧肿瘤中的炎症细胞死亡至关重要，为RNF213的调控提供了新的见解，并对莫亚莫亚病、炎症性疾病和自身免疫性疾病的发病机制具有潜在的影响。
原文链接
Bhardwaj A, Panepinto MC, Ueberheide B, Neel BG. A mechanism for hypoxia-induced inflammatory cell death in cancer. Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08136-y. Epub ahead of print. PMID: 39506105.
