Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Nat Commun. 2012;3:978. doi: 10.1038/ncomms1981.
Fas-associated protein with death domain (FADD) is a pivotal component of death receptor-mediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation. MKRN1 knockdown results in FADD protein stabilization and formation of the rapid death-inducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that MKRN1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of MKRN1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using MDA-MB-231 breast cancer cells. Suppression of tumour growth by MKRN1 depletion is relieved by simultaneous FADD knockdown. Our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway.
死亡结构域相关 Fas 相关蛋白（FADD）是死亡受体介导的细胞外凋亡和坏死性细胞死亡的关键组成部分。在这里，我们表明 FADD 受到含 Makorin 环指蛋白 1（MKRN1）E3 连接酶介导的泛素化和蛋白酶体降解的调节。MKRN1 敲低导致 FADD 蛋白稳定，并形成快速死亡诱导信号复合物，通过促进半胱天冬酶-8 和半胱天冬酶-3 的切割来响应死亡信号，从而导致对外源凋亡的敏感性增加。我们还表明，MKRN1 和 FADD 参与了 caspase 抑制后坏死小体形成和坏死性细胞死亡的调节。在使用 MDA-MB-231 乳腺癌细胞的异种移植模型中，MKRN1 的下调导致肿瘤坏死因子相关凋亡诱导配体处理后肿瘤生长严重缺陷。同时敲低 FADD 可缓解 MKRN1 耗竭引起的肿瘤生长抑制。我们的数据揭示了一种通过泛素化诱导降解途径调节 Fas 相关蛋白死亡结构域的新机制。
