Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Comprehensive Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Leukemia. 2016 Mar;30(3):716-27. doi: 10.1038/leu.2015.267. Epub 2015 Oct 6.
Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc-finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL.
成人 T 细胞白血病（ATL）源自人类 T 细胞白血病病毒 1 型（HTLV-I）感染的细胞，治疗选择有限。在这里，我们揭示了泛素编辑酶 A20 在 HTLV-I 感染细胞存活中的一个先前未被认识的作用。与 B 细胞谱系的淋巴瘤不同，A20 在原发性 ATL 细胞中大量表达，没有明显的突变。在 HTLV-I 感染的细胞中耗尽 A20 会导致半胱天冬酶激活、细胞死亡诱导和在小鼠异种移植模型中的肿瘤发生能力受损。在机制上，A20 在 HTLV-I 感染的细胞中与 caspase-8 和 Fas 相关 via death domain（FADD）稳定相互作用。突变研究表明，A20 支持 HTLV-I 感染细胞的生长，不依赖于其催化功能，锌指结构域对于与半胱天冬酶的相互作用和调节是必需的。这些结果表明 A20 在 HTLV-I 感染细胞的存活中起着关键作用，并暗示 A20 是 ATL 的一个潜在治疗靶点。
