Tortola Luigi, Nitsch Roberto, Bertrand Mathieu J M, Kogler Melanie, Redouane Younes, Kozieradzki Ivona, Uribesalgo Iris, Fennell Lilian M, Daugaard Mads, Klug Helene, Wirnsberger Gerald, Wimmer Reiner, Perlot Thomas, Sarao Renu, Rao Shuan, Hanada Toshikatsu, Takahashi Nozomi, Kernbauer Elisabeth, Demiröz Duygu, Lang Michaela, Superti-Furga Giulio, Decker Thomas, Pichler Andrea, Ikeda Fumiyo, Kroemer Guido, Vandenabeele Peter, Sorensen Poul H, Penninger Josef M
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
Cell Rep. 2016 May 17;15(7):1481-1492. doi: 10.1016/j.celrep.2016.04.032. Epub 2016 May 5.
The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway.
HECT结构域E3连接酶HACE1已被确定为多种癌症中的肿瘤抑制因子。在此，我们报告HACE1是TNFR1诱导的细胞命运的核心守门人。HACE1的基因失活会抑制TNF刺激的NF-κB激活以及体内TNFR1-NF-κB依赖性病原体清除。此外，在体内hace1突变细胞和基因敲除小鼠中，TNF诱导的细胞凋亡受损。从机制上讲，HACE1对于衔接蛋白TRAF2的泛素化以及凋亡半胱天冬酶-8效应复合物的形成至关重要。有趣的是，HACE1的缺失并不损害TNFR1通过RIP1和RIP3激酶介导的坏死性凋亡细胞命运。HACE1的缺失使动物在体内易患结肠炎症和癌症，而RIP3激酶和TNFR1的基因失活可显著缓解这种情况。因此，HACE1控制TNF引发的细胞命运决定，并通过TNFR1-RIP3激酶-坏死性凋亡途径发挥肿瘤抑制和抗炎活性。
