Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells
Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells
复制标题
DOI：
10.1172/jci37155
复制
发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Hartmann, Gunther
中科院分区：
文献类型：
--
作者：
Besch, Robert;Poeck, Hendrik;Hartmann, Gunther
视黄酸诱导基因I（RIG-1）和黑色素瘤分化相关抗原5（MDA-5）解旋酶在感染的细胞中感测病毒RNA并启动抗病毒应答，例如I型IFN的产生。在这里，我们已经证明RIG-I和MDA-5也启动了独立于I型IFN的促细胞凋亡信号通路。在人类黑色素瘤细胞中，这种信号通路需要线粒体衔接子Cardif（也称为IPS-1），并诱导促细胞凋亡的仅含BH 3的蛋白质Puma和Noxa。RIG-1和MDA-5启动的细胞凋亡需要Noxa，但不依赖于肿瘤抑制因子p53。触发该途径导致线粒体凋亡的有效激活，需要caspase-9和Apaf-1。令人惊讶的是，这种促凋亡信号通路在非恶性细胞中也很活跃，但这些细胞对凋亡的敏感性比黑色素瘤细胞低得多。内源性Bcl-X（L）可挽救非恶性细胞（但不能挽救黑色素瘤细胞）免于RIG-I和MDA-5介导的凋亡。此外，我们证实了体外研究的结果，证明RIG-I和MDA-5配体都减少了免疫缺陷NOD/SCID小鼠中的人肿瘤肺转移。这些结果鉴定了由RIG-1和MDA-5启动的IFN-依赖性抗病毒信号传导途径，其激活促凋亡信号传导，并且除非被Bcl-X（L）阻断，否则导致凋亡。由于它们的免疫刺激和促凋亡活性，RIG-I和MDA-5配体具有治疗潜力，因为它们能够克服黑素瘤细胞对凋亡的特征性抗性。
The retinoic acid-inducible gene I (RIG-1) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs. Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-1- and MDA-5-initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-X(L) rescued nonmalignant, but not melanoma, cells from RIG-I- and MDA-5-mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-1 and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-X(L), results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.