美国纽约大学格罗斯曼医学院Abhishek Bhardwaj团队近期取得重要工作进展，他们研究提出了癌症中缺氧诱导炎症细胞死亡的机制。相关研究成果2024年11月6日在线发表于《自然》杂志上。

据介绍，缺氧癌症细胞抵抗许多抗肿瘤治疗，并可能导致复发。

研究人员之前发现蛋白酪氨酸磷酸酶（PTP1B）的缺乏或抑制通过激活RNF213（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）促进人表皮生长因子受体2阳性乳腺癌症细胞在缺氧时死亡，RNF213与烟雾病、脂毒性和先天免疫有关。

研究人员发现，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结构域普遍存在并诱导NF-κB主要调节因子CYLD/SPATA2的降解。CYLD/SPATA2水平的降低导致NF-κB活化和NLRP3炎性小体的诱导，再加上缺氧诱导的内质网应激，引发焦亡细胞死亡。与该模型一致，CYLD缺失表型，而NLRP3缺失阻断PTP1B缺乏对人表皮生长因子受体2阳性乳腺癌症异种移植物生长的影响。对RNF213突变体的重组研究证实，RZ结构域介导肿瘤细胞死亡。

总之，这一研究结果确定了一种独特的、潜在可靶向的PTP1B-RNF213-CYLD-SPATA2通路，该通路对控制缺氧性肿瘤中的炎性细胞死亡至关重要，为RNF213调控提供了新的见解，并对烟雾病、炎性疾病和自身免疫性疾病的发病机制具有潜在意义。

附：英文原文

Title: A mechanism for hypoxia-induced inflammatory cell death in cancer

Author: Bhardwaj, Abhishek, Panepinto, Maria C., Ueberheide, Beatrix, Neel, Benjamin G.

Issue&Volume: 2024-11-06

Abstract: Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence1,2. We previously found that either deficiency or inhibition of protein-tyrosine phosphatase (PTP1B) promotes human epidermal growth factor receptor2-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 receptor2-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.

DOI: 10.1038/s41586-024-08136-y

Source: https://www.nature.com/articles/s41586-024-08136-y