Male hormones activate EphA2 to facilitate Kaposi's sarcoma-associated herpesvirus infection: Implications for gender disparity in Kaposi's sarcoma.
Male hormones activate EphA2 to facilitate Kaposi's sarcoma-associated herpesvirus infection: Implications for gender disparity in Kaposi's sarcoma.
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DOI：
10.1371/journal.ppat.1006580
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发表时间：
2017-09
期刊：
影响因子：
6.7
通讯作者：
Lan K
中科院分区：
文献类型：
--
作者：
Wang X;Zou Z;Deng Z;Liang D;Zhou X;Sun R;Lan K
越来越多的共识是，男性比女性更容易受到几种病原体的感染。然而，其内在机制需要进一步研究。在此，研究表明，雄激素受体（AR）表达的敲低或用AR激动剂5α-二氢睾酮预处理，导致卡波西肉瘤相关疱疹病毒（KSHV）感染显著失调。在内皮细胞中，膜定位AR促进KSHV的内吞和核运输。AR与肝配蛋白受体A2（EphA 2）相互作用并增加其在残基Ser 897处的磷酸化，这在KSHV感染后特异性上调。这种磷酸化是由AR介导的Src募集引起的，这导致p90核糖体S6激酶1（RSK 1）的激活，其直接使EphA 2在Ser 897处磷酸化。最后，在Ser 897 Asn EphA 2突变体中消除了EphA 2介导的KSHV进入。总之，膜定位AR被鉴定为KSHV进入因子，其协同激活Src/RSK 1/EphA 2信号传导，随后促进内皮细胞和上皮细胞的KSHV感染。虽然KS发病率在男性中较高，这与血液中较高的血清阳性率和病毒DNA水平相关，但很少有人知道男性性类固醇是否会导致这种差异。在本研究中，我们已经证实了AR及其配体在促进KSHV在靶细胞中的初次感染中的作用。具体而言，AR抑制导致在KSHV早期进入阶段核周积累的病毒颗粒的数量急剧减少。从机制上讲，这种作用是由于AR与已知的KSHV受体EphA 2相互作用并刺激信号转导所致。AR募集Src，激活RSK 1，然后增加EphA 2在残基Ser 897处的磷酸化，这是成功感染KSHV的先决条件。我们的研究首次提供了一个独特的见解，为什么KSHV可能在男性中的患病率较高。
There is increasing consensus that males are more vulnerable than females to infection by several pathogens. However, the underlying mechanism needs further investigation. Here, it was showed that knockdown of androgen receptor (AR) expression or pre-treatment with 5α-dihydrotestosterone, the AR agonist, led to a considerably dysregulated Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. In endothelial cells, membrane-localized AR promoted the endocytosis and nuclear trafficking of KSHV. The AR interacted with ephrin receptor A2 (EphA2) and increased its phosphorylation at residue Ser897, which was specifically upregulated upon KSHV infection. This phosphorylation resulted from the AR-mediated recruitment of Src, which resulted in the activation of p90 ribosomal S6 kinase 1 (RSK1), which directly phosphorylates EphA2 at Ser897. Finally, the EphA2-mediated entry of KSHV was abolished in a Ser897Asn EphA2 mutant. Taken together, membrane-localized AR was identified as a KSHV entry factor that cooperatively activates Src/RSK1/EphA2 signaling, which subsequently promotes KSHV infection of both endothelial and epithelial cells. Although KS incidence is higher in males, which correlates with higher seroprevalence and viral DNA levels in the blood, little is known whether male sex steroids contribute to this disparity. In the present study, we have confirmed the role of both AR and its ligand in promoting KSHV primary infection in target cells. Specifically, AR inhibition led to a dramatically decreased number of perinuclear-accumulated virus particles during early KSHV entry stage. Mechanically speaking, the effect was resulted from the interaction of AR with known KSHV receptor EphA2 and stimulating signal transduction. The AR recruited Src, activated RSK1, and then increased EphA2 phosphorylation at residue Ser897, which is prerequisite for successful KSHV infection. Our study provides for the first time a unique insight into why KSHV may have a higher prevalence in males.
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影响因子：
6.7
作者：
Greene W;Gao SJ
通讯作者：
Gao SJ
DOI：
10.1073/pnas.1119592109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Chakraborty, Sayan;Veettil, Mohanan Valiya;Chandran, Bala
通讯作者：
Chandran, Bala
影响因子：
4.8
作者：
Cinar, Bekir;Mukhopadhyay, Nishit K.;Freeman, Michael R.
通讯作者：
Freeman, Michael R.
影响因子：
5.2
作者：
Chakraborty S;Veettil MV;Chandran B
通讯作者：
Chandran B
影响因子：
4.4
作者：
Mielenz, D;Vettermann, C;Jäck, HM
通讯作者：
Jäck, HM