PO.TB10.16 · 肿瘤生物学
DAPK3-DCAF1通路调控ZBP1蛋白稳定性以协调固有免疫应答与PANoptosis
DAPK3-DCAF1 pathway regulates ZBP1 protein stability to orchestrate innate immune responses and PANoptosis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Z-DNA结合蛋白1（ZBP1）是一种干扰素（IFN）诱导的Z-核酸（Z-NA）胞质感受器，可调控PANoptosis（细胞焦亡、凋亡和/或坏死性凋亡），从而驱动强效的抗肿瘤免疫应答。然而，控制肿瘤中ZBP1蛋白稳定性的机制，以及能否通过治疗手段对其进行操纵以诱导免疫原性细胞死亡（ICD），目前仍不清楚。我们旨在明确调控卵巢癌中ZBP1丰度的调节通路，并检验利用ZBP1激活进行抗肿瘤治疗的策略。
方法与结果：本研究中我们证明，卵巢癌中ZBP1表达降低，并与较差的生存相关。I型IFN（IFN-beta）通过抑制ZBP1的蛋白酶体依赖性泛素化，迅速升高其水平。邻近标记与生化实验鉴定出DCAF1是介导ZBP1泛素化与降解的关键相互作用蛋白。此外，IP-MS与LC-MS/MS鉴定出DAPK3是一种IFN诱导的DCAF1激酶，其磷酸化DCAF1-pS1328以促进其周转，从而稳定ZBP1。DCAF1的基因敲除在体外损害了肿瘤细胞增殖，在体内降低了肿瘤负荷并促进了抗肿瘤免疫。使用DCAF1抑制剂B32B3对该通路进行药理学靶向——并与Z-NA激活剂CBL0137联用时——可有效重新激活ZBP1信号、促进PANoptosis并增强抗肿瘤免疫，从而在两个化疗耐药的卵巢癌患者来源异种移植（PDX）模型中抑制肿瘤生长，为难治性恶性肿瘤提供了一种有前景的治疗策略。
结论：总体而言，本研究勾勒出一条新型的DAPK3-DCAF1信号轴，其调控ZBP1稳定性，揭示了一个连接干扰素信号、翻译后修饰与免疫原性细胞死亡的整合调控框架。将DCAF1阻断与Z-NA激活相结合，可引发ZBP1介导的PANoptosis并增强抗肿瘤免疫，代表了一种针对难治性卵巢癌的有前景的治疗方法。
查看英文原文 English abstract
Background: Z-DNA binding protein 1 (ZBP1) is an interferons (IFN)-stimulated cytosolic sensor of Z-nucleic acids (Z-NA) that regulates PANoptosis (pyroptosis, apoptosis, and/or necroptosis) and thereby drives potent anti-tumor immune responses. However, the mechanisms controlling ZBP1 protein stability in tumors-and whether they can be therapeutically manipulated to induce ICD-remain unclear. We sought to define regulatory pathways that govern ZBP1 abundance in ovarian cancer and to test strategies that exploit ZBP1 activation for antitumor therapy.
Methods & Results: Here we demonstrate that the reduced ZBP1 expression in ovarian cancer and correlated with poorer survival. Type I IFN (IFN-beta) rapidly increased ZBP1 levels by inhibiting its proteasome-dependent ubiquitination. Proximity labeling and biochemical assays identified DCAF1 as a key interactor that mediates ZBP1 ubiquitination and degradation. Furthermore, IP-MS and LC-MS/MS identified DAPK3 as an IFN-induced DCAF1 kinase, which phosphorylates DCAF1-pS1328 to promote its turnover, thereby stabilizing ZBP1. Genetic ablation of DCAF1 impaired tumor cell proliferation in vitro , reduced tumor burden and promoted anti-tumor immunity in vivo . Pharmacological targeting of this pathway using the DCAF1 inhibitor B32B3 and-when combined with the Z-NA activator CBL0137-effectively reactivated ZBP1 signaling, promoted PANoptosis, and enhanced antitumor immunity, thereby suppressing tumor growth in two chemotherapy-resistant ovarian cancer patient-derived xenograft (PDX) models and providing a promising therapeutic strategy for refractory malignancies.
Conclusion: Overall, this study delineates a novel DAPK3-DCAF1 signaling axis that governs ZBP1 stability, unveiling an integrated regulatory framework that connects interferon signaling, post-translational modification, and immunogenic cell death. Combining DCAF1 blockade with Z-NA activation elicits ZBP1-mediated PANoptosis and augments anti-tumor immunity, representing a promising therapeutic approach for refractory ovarian cancer.
利益披露 Disclosure
Z. Liao, None..
L. Wang, None..
W. Gong, None..
Z. Zhang, None..
D. Ma, None..
G. Zhao, None..
Q. Gao, None..
Y. Fang, None.