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ADAR1阻止ZBP1驱动的坏死性凋亡
2022-05-29 15:09
来源：小柯机器人

美国福克斯切斯癌症中心Siddharth Balachandran、俄罗斯国立高等经济大学Alan Herbert等研究人员合作发现，ADAR1可阻止ZBP1驱动的坏死性凋亡。该项研究成果于2022年5月25日在线发表在《自然》杂志上。

研究人员表示，只有一小部分癌症患者对基于免疫检查点阻断（ICB）的单项疗法有持久的反应。RNA编辑酶ADAR1是一个新出现的决定性因素，它通过抑制免疫原性双链RNA（dsRNA），如那些由内源性逆转录病毒元件（ERE）表达失调而产生的双链RNA来防止ICB反应。这些dsRNA通过激活A型dsRNA（A-RNA）感应蛋白，如MDA-5和PKR5，引发干扰素依赖性抗肿瘤反应。
 
研究人员发现，ADAR1也阻止了内源性Z型dsRNA元件（Z-RNA）的累积，这些元件在干扰素刺激的mRNA的3′非翻译区富集。ADAR1的耗尽或突变导致Z-RNA的积累和Z-RNA传感器ZBP1的激活，最终导致了RIPK3介导的坏死性凋亡。由于目前没有临床上可行的ADAR1抑制剂，研究人员寻找了一种能推翻对ADAR1抑制要求并直接激活ZBP1的化合物。研究人员发现了一种小分子，即curaxin CBL0137，它通过触发细胞中的Z-DNA形成来有效地激活ZBP1。CBL0137在癌症相关的成纤维细胞中诱导ZBP1依赖性的坏死性凋亡，并在黑色素瘤的小鼠模型中逆转了ICB的无反应性。
 
总之，这些结果表明，ADAR1抑制内源性Z-RNA，并确定ZBP1介导的坏死性凋亡是被ADAR1掩盖的肿瘤免疫原性的一个新决定因素。ZBP1诱导的坏死性凋亡的治疗性激活为重启ICB抗性人类癌症的免疫反应性，提供了一个容易转化的途径。
 
附：英文原文
 
Title: ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

Author: Zhang, Ting, Yin, Chaoran, Fedorov, Aleksandr, Qiao, Liangjun, Bao, Hongliang, Beknazarov, Nazar, Wang, Shiyu, Gautam, Avishekh, Williams, Riley M., Crawford, Jeremy Chase, Peri, Suraj, Studitsky, Vasily, Beg, Amer A., Thomas, Paul G., Walkley, Carl, Xu, Yan, Poptsova, Maria, Herbert, Alan, Balachandran, Siddharth

Issue&Volume: 2022-05-25

Abstract: Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs)1,2,3,4. These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5. Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3′untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers.

DOI: 10.1038/s41586-022-04753-7

Source: https://www.nature.com/articles/s41586-022-04753-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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