Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity.
Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity.
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DOI：
10.1371/journal.ppat.1000157
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发表时间：
2008-09-19
期刊：
影响因子：
6.7
通讯作者：
Feng P
中科院分区：
文献类型：
--
作者：
Feng H;Dong X;Negaard A;Feng P
卡波西肉瘤相关疱疹病毒（KSHV）基因组编码G蛋白偶联受体（vGPCR）。vGPCR是一种非配体依赖性的组成型活性信号分子，可促进细胞生长和增殖;然而，目前尚不清楚vGPCR是如何负调控的。我们在这里报告，KSHV K7小膜蛋白与vGPCR相互作用，并诱导其降解，从而抑制vGPCR信号。在瞬时转染的人细胞中容易检测到K7与vGPCR的相互作用。突变分析表明，K7跨膜结构域是必要的和充分的这种相互作用。生化和共聚焦显微镜研究表明，K7保留vGPCR在内质网（ER）和诱导vGPCR蛋白酶体降解。事实上，通过shRNA介导的沉默敲低K7增加了诱导KSHV裂解复制的BCBL-1细胞中的vGPCR蛋白表达。有趣的是，K7表达显著降低了裸鼠中vGPCR的致瘤性。这些发现定义了负调节vGPCR蛋白表达的病毒因子，并揭示了调节GPCR依赖性转化和致瘤性的翻译后事件。卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤的病原体。KSHV也见于原发性渗出性淋巴瘤和多中心性Castleman病，罕见的与免疫抑制相关的淋巴组织增生性疾病。KSHV基因组编码一种G蛋白偶联受体（vGPCR），据信该受体与KSHV相关的恶性肿瘤有关。vGPCR是配体非依赖性的组成型活性信号分子。目前尚不清楚vGPCR是如何负调控的。在这里，我们报告KSHV小膜K7蛋白通过其假定的跨膜结构域与vGPCR相互作用。与K7的相互作用将vGPCR保留在ER中，并促进其被蛋白酶体降解，从而降低vGPCR蛋白表达。因此，K7显著减少vGPCR介导的体外转化和裸鼠中的肿瘤形成。我们的研究结果表明，K7的功能作为一种病毒因子，抑制vGPCR蛋白的表达和负调节肿瘤诱导能力的vGPCR，这意味着KSHV已经进化的机制，以避免有害影响，并允许在其宿主内持续感染。
The Kaposi's sarcoma-associated herpesvirus (KSHV) genome encodes a G protein-coupled receptor (vGPCR). vGPCR is a ligand-independent, constitutively active signaling molecule that promotes cell growth and proliferation; however, it is not clear how vGPCR is negatively regulated. We report here that the KSHV K7 small membrane protein interacts with vGPCR and induces its degradation, thereby dampening vGPCR signaling. K7 interaction with vGPCR is readily detected in transiently transfected human cells. Mutational analyses reveal that the K7 transmembrane domain is necessary and sufficient for this interaction. Biochemical and confocal microscopy studies indicate that K7 retains vGPCR in the endoplasmic reticulum (ER) and induces vGPCR proteasomeal degradation. Indeed, the knockdown of K7 by shRNA-mediated silencing increases vGPCR protein expression in BCBL-1 cells that are induced for KSHV lytic replication. Interestingly, K7 expression significantly reduces vGPCR tumorigenicity in nude mice. These findings define a viral factor that negatively regulates vGPCR protein expression and reveal a post-translational event that modulates GPCR-dependent transformation and tumorigenicity. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma. KSHV is also found in primary effusion lymphoma and multicentric Castleman's disease, rare lymphoproliferative diorders associated with immuno-suppression. The KSHV genome encodes a G protein-coupled receptor (vGPCR) that is believed to contribute to the KSHV-associated malignancies. vGPCR is a ligand-independent, constitutively active signaling molecule. It is not clear how vGPCR is negatively regulated. Here, we report that the KSHV small membrane K7 protein interacts with vGPCR through its putative transmembrane domain. Interaction with K7 retains vGPCR in the ER and facilitates its degradation by the proteasome, thereby reducing vGPCR protein expression. Consequently, K7 significantly reduces vGPCR-mediated transformation in vitro and tumor formation in nude mice. Our findings reveal that K7 functions as a viral factor to dampen vGPCR protein expression and negatively modulate the tumor-inducing capacity of vGPCR, implying that KSHV has evolved mechanisms to avoid deleterious effects and to permit persistent infection within its host.
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影响因子：
5.4
作者：
Feng, PH;Park, J;Jung, JU
通讯作者：
Jung, JU
DOI：
10.1084/jem.187.5.801
发表时间：
1998-03-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Geras-Raaka E;Arvanitakis L;Bais C;Cesarman E;Mesri EA;Gershengorn MC
通讯作者：
Gershengorn MC
影响因子：
64.8
作者：
Lilley, BN;Ploegh, HL
通讯作者：
Ploegh, HL
DOI：
10.1006/bbrc.1998.9557
发表时间：
1998-12-30
影响因子：
3.1
作者：
Geras-Raaka, E;Varma, A;Gershengorn, MC
通讯作者：
Gershengorn, MC
影响因子：
82.9
作者：
Lee, H;Veazey, R;Jung, JU
通讯作者：
Jung, JU