CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation.
CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation.
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DOI：
10.1371/journal.ppat.1006968
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发表时间：
2018-04
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：
Hunte R;Alonso P;Thomas R;Bazile CA;Ramos JC;van der Weyden L;Dominguez-Bendala J;Khan WN;Shembade N
全世界大约12%的人类癌症是由致癌病毒感染引起的。Kaposi肉瘤疱疹病毒/人类疱疹病毒8型(KSHV/HHV8)是引起人类肿瘤的致癌病毒之一，包括Kaposi肉瘤(KS)、原发性渗出性淋巴瘤(PEL)和淋巴组织增生性疾病多中心Castleman病(MCD)。KSHV感染介导的慢性炎症在这些癌症的发展和生存中起着决定性的作用。核因子-κB是一个调节炎症、细胞存活和增殖的转录因子家族，在感染KSHV的细胞中持续激活。参与NF-κB激活的KSHV潜伏表达癌基因和裂解表达癌基因分别为vFlIP/K13和vGPCR3。然而，vFlIP和vGPCR激活NF-κB的机制尚不清楚。在这项研究中，我们发现宿主分子细胞黏附分子1(CADM1)在KSHV感染的PBMC和KSHV相关的PEL细胞中强烈上调。进一步的研究确定vFlIP和vGPCR都与CADM1相互作用。位于CADM1羧基末端的PDZ结合基序对于vGPCR和vFlIP维持慢性NF-κB激活是必不可少的。膜脂筏相关的CADM1与vFlIP的相互作用是细胞内IKK激酶复合体的启动和NF-κB活化的关键。此外，CADM1在KSHV相关PEL细胞的存活中起着至关重要的作用。这些数据表明，CADM1在KSHV生命周期潜伏期和裂解期的NF-κB通路的激活以及感染KSHV的细胞的生存中起关键作用。Kaposi肉瘤疱疹病毒(KSHV)感染导致Kaposi肉瘤(KS)、原发性渗出性淋巴瘤(PEL)、多中心Castleman病(MCD)和艾滋病相关Kaposi肉瘤(AIDS-KS)的发生。KSHV感染表现为潜伏期和裂解期，病毒基因表达明显不同。在KSHV潜伏期和裂解期，转录因子NF-κB介导的慢性炎症在KSHV相关恶性肿瘤的发生发展中起着关键作用。KSHV感染细胞持续激活的主要机制之一是病毒癌基因对宿主基因表达及其正常功能的失调。然而，KSHV感染细胞中持续激活NF-κB所需的细胞宿主因素和机制在很大程度上仍不清楚。在这里，我们专注于宿主肿瘤抑制因子细胞黏附分子1(CADM1)，它在KSHV感染后几个小时内强烈上调。尽管CADM1在实体瘤中作为肿瘤抑制因子的作用尚不完全清楚，但它在致癌病毒介导的肿瘤中的作用却知之甚少。我们研究了CADM1在KSHV感染细胞中持续的NF-κB激活中的作用。我们发现，KSHV的潜伏癌基因和裂解癌基因vFlIP和vGPC都需要CADM1来维持慢性NF-κB的激活。我们进一步证明了CADM1对于KSHV相关的PEL细胞的生存至关重要。我们的研究揭示了CADM1CADM1在KSHV感染细胞中慢性激活NF-κB的新机制。
Approximately 12% of all human cancers worldwide are caused by infections with oncogenic viruses. Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) is one of the oncogenic viruses responsible for human cancers, including Kaposi’s sarcoma (KS), Primary Effusion Lymphoma (PEL), and the lymphoproliferative disorder multicentric Castleman’s disease (MCD). Chronic inflammation mediated by KSHV infection plays a decisive role in the development and survival of these cancers. NF-κB, a family of transcription factors regulating inflammation, cell survival, and proliferation, is persistently activated in KSHV-infected cells. The KSHV latent and lytic expressing oncogenes involved in NF-κB activation are vFLIP/K13 and vGPCR, respectively. However, the mechanisms by which NF-κB is activated by vFLIP and vGPCR are poorly understood. In this study, we have found that a host molecule, Cell Adhesion Molecule 1 (CADM1), is robustly upregulated in KSHV-infected PBMCs and KSHV-associated PEL cells. Further investigation determined that both vFLIP and vGPCR interacted with CADM1. The PDZ binding motif localized at the carboxyl terminus of CADM1 is essential for both vGPCR and vFLIP to maintain chronic NF-κB activation. Membrane lipid raft associated CADM1 interaction with vFLIP is critical for the initiation of IKK kinase complex and NF-κB activation in the PEL cells. In addition, CADM1 played essential roles in the survival of KSHV-associated PEL cells. These data indicate that CADM1 plays key roles in the activation of NF-κB pathways during latent and lytic phases of the KSHV life cycle and the survival of KSHV-infected cells. Infection with Kaposi sarcoma herpesvirus (KSHV) leads to the development of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and AIDS-associated Kaposi's sarcoma (AIDS-KS). KSHV infection exhibits both latent and lytic phases with distinct viral gene expression. Chronic inflammation mediated by a transcription factor, NF-κB, during KSHV latent and lytic phases play critical roles in the development of KSHV-associated malignancies. One of the main mechanisms of persistent NF-κB activation in KSHV-infected cells is dysregulation of host gene expression and their normal functions by viral oncogenes. However, the cellular host factors and the mechanisms required for persistent NF-κB activation in KSHV-infected cells remains largely unknown. Here, we focused on host tumor suppressor Cell adhesion molecule 1 (CADM1) that is robustly upregulated within a few hours of KSHV infection. Although the role of CADM1 as a tumor suppressor in solid tumors is partially known, its role in oncogenic virus-mediated tumors is poorly understood. We characterized the role of CADM1 in persistent NF-κB activation in KSHV infected cells. We found that CADM1 is required for both latent and lytic, vFLIP and vGPCR, oncogenes of KSHV to maintain chronic NF-κB activation. We further demonstrated that CADM1 is critical for the survival of KSHV-associated PEL cells. Our study reveals a novel mechanism of chronic NF-κB activation by CADM1 in KSHV-infected cells.
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