HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.
HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.
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HTLV-1 Tax 功能作为泛素 E3 连接酶，通过合成混合连接多泛素链直接激活 IKK
DOI：
10.1371/journal.ppat.1005584
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Wang C;Long W;Peng C;Hu L;Zhang Q;Wu A;Zhang X;Duan X;Wong CC;Tanaka Y;Xia Z
HTLV-1癌蛋白Tax主要通过永久激活NK-κB通路和诱导许多NF-κB靶基因，通过促进细胞增殖和存活，在CD4+ T细胞转化中发挥关键作用。因此，阐明潜在的分子机制对于理解htlv -1介导的转化至关重要。目前的研究提出了多种有争议的税收诱导的IKK激活机制，主要是由于税收诱导的IKK原发性激活事件和由税收诱导的IKK- nf -κB原发性激活事件分泌的细胞因子诱导的继发性IKK激活事件的混合。我们在无细胞系统中重建了税收刺激的IKK激活，剖析了税收刺激IKK激活的基本细胞成分，并研究了潜在的生化机制。我们发现Tax是一种假定的E3泛素连接酶，它与UbcH2、ubch5c或UbcH7一起催化自由混合连锁多泛素链的组装。这些自由的混合连锁多泛素链通过结合IKK的NEMO亚基直接激活IKK。我们的研究揭示了Tax在IKK激活过程中的生化功能，它利用最小的细胞泛素化成分激活NF-κB。人类T细胞白血病病毒1型（HTLV-1）是热带痉挛性截瘫/HTLV-1相关脊髓病（TSP/HAM）的病因，TSP/HAM是一种明显的神经系统疾病，伴有炎症症状和肢体不完全瘫痪，而成人T细胞白血病/淋巴瘤（ATL）是一种高度侵袭性的CD4+ T淋巴细胞恶性增殖。TSP/HAM和ATL主要由HTLV-1癌蛋白Tax刺激i -κB激酶(IKK)-NF-κB活化驱动。Tax激活IKK的分子机制尚不清楚。在这里，我们发现Tax是一种E3泛素连接酶，它与其同源的泛素偶联酶（E2s） UbcH2、UhcH5c或UbcH7一起，催化无锚定的自由混合连锁多泛素链的组装。多泛素链可以通过结合NEMO亚基直接激活IKK复合物。我们的研究揭示了HTLV-1在感染和发病过程中劫持的重要细胞因子，以及在IKK激活过程中Tax的生化功能和潜在机制。我们的工作可能为TSP/HAM和ATL治疗方法的潜在开发提供启示。
The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation. Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a distinct neurological disorder with inflammatory symptoms and incomplete paralysis of the limbs, and adult T-cell leukemia/lymphoma (ATL), a highly aggressive malignant proliferation of CD4+ T lymphocytes. Both TSP/HAM and ATL are mainly driven by the activation of IκB kinase (IKK)-NF-κB stimulated by HTLV-1 oncoprotein Tax. The molecular mechanism by which Tax activates IKK remains unclear. Here, we found that Tax is an E3 ubiquitin ligase, which, together with its cognate ubiquitin-conjugating enzymes (E2s) UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of unanchored free mixed-linkage polyubiquitin chains. The polyubiquitin chains can activate IKK complex directly by binding to the NEMO subunit. Our studies uncovered the essential cellular factors hijacked by HTLV-1 for infection and pathogenesis, as well as the biochemical function and the underlying mechanism of Tax in the process of IKK activation. Our work might shed light on potential development of therapeutics for TSP/HAM and ATL.