The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate.
The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate.
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肿瘤HACE1是TNFR1介导的细胞命运的关键调节剂。
DOI：
10.1016/j.celrep.2016.04.032
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发表时间：
2016-05-17
期刊：
影响因子：
8.8
通讯作者：
Penninger JM
中科院分区：
文献类型：
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作者：
Tortola L;Nitsch R;Bertrand MJM;Kogler M;Redouane Y;Kozieradzki I;Uribesalgo I;Fennell LM;Daugaard M;Klug H;Wirnsberger G;Wimmer R;Perlot T;Sarao R;Rao S;Hanada T;Takahashi N;Kernbauer E;Demiröz D;Lang M;Superti-Furga G;Decker T;Pichler A;Ikeda F;Kroemer G;Vandenabeele P;Sorensen PH;Penninger JM
HECT 结构域 E3 连接酶 HACE1 已被确定为多种癌症的肿瘤抑制因子。在此，我们报告 HACE1 是 TNFR1 诱导的细胞命运的中央看门人。 HACE1 的基因失活会抑制体内 TNF 刺激的 NF-κB 激活和 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 诱导的细胞凋亡受到损害。从机制上讲，HACE1 对于接头蛋白 TRAF2 的泛素化和凋亡 caspase-8 效应复合物的形成至关重要。有趣的是，HACE1 的缺失不会损害 TNFR1 通过 RIP1 和 RIP3 激酶介导的坏死性细胞命运。 HACE1 的缺失会使动物在体内容易发生结肠炎症和癌变，而 RIP3 激酶和 TNFR1 的基因失活可显着缓解这种情况。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。 Hace1 缺陷会损害 TNF 驱动的 NF-κB 激活和细胞凋亡 在缺乏 Hace1 的情况下，通过 RIP1/RIP3/MLKL 实现的坏死性凋亡仍然发挥作用 Hace1–/– 动物表现出结肠炎和结肠癌的严重程度增强 RIP3 和 TNFR1 的基因失活可恢复 hace1–/– 小鼠的表型 Tortola 等人。报道称，E3 泛素连接酶 HACE1 是 TNFR1 介导的细胞命运的看门人。 Hace1 缺陷会损害 TNF 驱动的 NF-κB 激活和细胞凋亡，并使细胞易于坏死性凋亡。因此，hace1–/– 小鼠表现出增强的结肠炎和结肠癌，这可以通过促坏死性激酶 RIP3 和 TNFR1 的失活来逆转。
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. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis Necroptosis via RIP1/RIP3/MLKL is still functional in the absence of Hace1 Hace1–/– animals show enhanced severity of colitis and colon cancer Genetic inactivation of RIP3 and TNFR1 reverts the phenotype of hace1–/– mice Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1–/– mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.