Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.
Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.
复制标题
DOI：
10.1371/journal.ppat.1004721
复制
发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Shembade N
中科院分区：
文献类型：
--
作者：
Pujari R;Hunte R;Thomas R;van der Weyden L;Rauch D;Ratner L;Nyborg JK;Ramos JC;Takai Y;Shembade N
人T细胞白血病病毒1型（HTLV-1）癌蛋白Tax对NF-κB的持续激活在成人T细胞白血病（ATL）和HTLV-1相关性脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）的发生和发病机制中至关重要。K63连接的多聚泛素化Tax激活质膜相关脂筏微结构域中的IKK复合物Tax还与TAX 1BP 1相互作用，以抑制NF-κB负调控泛素编辑A20酶复合物。然而，Tax介导的IKK激活和A20蛋白复合物失活的分子机制知之甚少。在这里，我们证明了膜相关的CADM 1（细胞粘附分子1）招募Ubc 13到Tax，导致K63连接的Tax的多聚泛素化，以及膜脂筏中IKK复合物的激活。CADM 1的C端胞质尾区含有PDZ结合基序，这对于Tax维持NF-κB的持续活化至关重要。最后，Tax未能激活NF-κB负调控泛素编辑酶A20复合物，并在缺乏CADM 1的情况下激活脂筏中的IKK复合物。因此，我们的结果表明，CADM 1作为Tax和Ubc 13的关键支架分子，与NEMO、TAX 1 BP 1和NRP形成细胞复合物，激活质膜相关脂筏中的IKK复合物，灭活NF-κB负调节因子，并维持持续的NF-κB活化HTLV-1感染细胞中的活化。B。HTLV-1感染导致成人T细胞白血病（ATL）或HTLV-1相关的脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）的发展。导致HTLV-1相关疾病发展的主要原因之一是由NF-κ B（NF-κB）指导的慢性炎症。NF-κB对多种信号的响应是短暂的，并受到泛素编辑酶A20的严格控制。在HTLV-1感染的细胞中持续的NF-κB活化的机制之一是NF-κB负调节剂的失活;然而，确切的机制尚不清楚。在这里，我们重点关注宿主肿瘤抑制因子细胞粘附分子1（CADM 1），它在HTLV-1感染的细胞中强烈上调。CADM 1的表达在几种癌症中经常沉默;然而，它对HTLV-1相关的ATL肿瘤细胞存活至关重要。我们表征了CADM 1在HTLV-1感染细胞中持续NF-κB活化中的作用。我们发现，CADM 1是HTLV-1癌蛋白Tax与Ubc 13、TAX 1BP 1、NRP和NEMO在膜脂筏微区形成细胞复合物所必需的。我们进一步证明Tax需要CADM 1抑制NF-κB负调控因子并维持NF-κB的持续活化。我们的研究揭示了在HTLV-1感染的细胞中CADM 1慢性激活NF-κB的新机制。
Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells. HTLV-1 infection leads to the development of Adult T-cell Leukemia (ATL) or HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). One of the major causes responsible for the development of HTLV-1 associated diseases is chronic inflammation directed by NF-kappaB (NF-κB). NF-κB activation in response to a wide variety of signals is transient and tightly controlled by ubiquitin-editing enzyme A20. One of the mechanisms of persistent NF-κB activation in HTLV-1 infected cells is inactivation of NF-κB negative regulators; however, the precise mechanism is unknown. Here, we focused on host tumor suppressor Cell adhesion molecule 1 (CADM1) that is robustly upregulated in HTLV-1 infected cells. The expression of CADM1 is frequently silenced in several cancers; however, it is critical for HTLV-1 associated ATL tumor cell survival. We characterized the role of CADM1 in persistent NF-κB activation in HTLV-1 infected cells. We found that CADM1 is required for the HTLV-1 oncoprotein, Tax, to form a cellular complex with Ubc13, TAX1BP1, NRP and NEMO in the membrane lipid rafts micorodomain. We further demonstrated that Tax requires CADM1 to inactivate NF-κB negative regulator and maintain persistent NF-κB activation. Our study reveals a novel mechanism of chronic NF-κB activation by CADM1 in HTLV-1 infected cells.
登录
查看更多内容
影响因子：
30.5
作者：
Gaide, O;Favier, B;Thome, M
通讯作者：
Thome, M
影响因子：
3.3
作者：
Ishioka, Kojiro;Higuchi, Masaya;Fujii, Masahiro
通讯作者：
Fujii, Masahiro
影响因子：
64.5
作者：
Jin, DY;Spencer, F;Jeang, KT
通讯作者：
Jeang, KT
影响因子：
5.4
作者：
Gao, Linlin;Harhaj, Edward William
通讯作者：
Harhaj, Edward William
影响因子：
6.4
作者：
Chen, Kequan;Wang, Guanghai;Zhang, Yali
通讯作者：
Zhang, Yali