中科院上海巴斯德研究所藍柯研究組在在皰疹病毒調(diào)控宿主炎癥反應(yīng)研究中取得新進展,，相關(guān)研究論文在線發(fā)表在6月22日國際病毒學(xué)知名學(xué)術(shù)期刊《病毒學(xué)期刊》（Journal of Virology）上,。
上海巴斯德研究所的博士研究生李小凡,、梁德光等是該論文的第一作者,，藍柯研究員為論文的通訊作者,。該研究課題得到了國家973計劃,、國家自然科學(xué)基金,、中國科學(xué)院“百人計劃” 以及賽諾菲-安萬特-中科院上海生命科學(xué)研究院優(yōu)秀青年人才基金項目的資助,。
卡波氏肉瘤相關(guān)皰疹病毒（Kaposi’s sarcoma associated herpesvirus, KSHV）是一種人類腫瘤病毒，是引起卡波氏肉瘤（Kaposi’s sarcoma, KS）,、原發(fā)性滲出性淋巴瘤（Primary effusion lymphoma, PEL）以及多中心性 Castleman?。∕ulticentric Castleman disease, MCD）的病原體,。KSHV 能夠成功地在宿主體內(nèi)建立終身潛伏感染,。以往的研究表明，從KSHV原發(fā)感染到建立潛伏感染的過程中,，KSHV編碼的一系列功能蛋白通過抑制宿主細胞的固有免疫應(yīng)答來逃避宿主的清除,，但對已經(jīng)建立潛伏感染的KSHV如何應(yīng)對其它病原體感染觸發(fā)的宿主急性炎癥反應(yīng)一直不清楚,。
在新研究中,，李小凡等發(fā)現(xiàn)KSHV潛伏感染或者過表達病毒潛伏基因LANA-1的血管內(nèi)皮細胞對促炎癥因子TNF-α的應(yīng)答受到明顯的抑制：TNF-α刺激后血管內(nèi)皮細胞IL-8的mRNA水平和細胞培養(yǎng)液中IL-8的含量較對照細胞有明顯的下調(diào)，并且細胞培養(yǎng)液對人中性粒細胞 (neutrophil)的趨化作用明顯降低,。報告基因研究表明,，LANA-1能有效地阻斷介導(dǎo)炎癥反應(yīng)的NF-κB信號通路,。進一步的工作揭示,，LANA-1能夠利用宿主細胞的多泛素化修飾介導(dǎo)的蛋白降解途徑,，特異地降解細胞核內(nèi)的NF-κB成員p65的蛋白水平，從而抑制NF-κB信號通路的激活,。具體地,，LANA-1與細胞核內(nèi)的p65相互作用，并將其招募至細胞泛素連接酶elonginB/C-cullin5復(fù)合體中,，增強p65的多泛素化修飾介導(dǎo)的降解,。
該工作揭示了KSHV重要的潛伏期相關(guān)基因LANA-1是急性炎癥反應(yīng)的負調(diào)控因子，深化了人們對于KSHV和宿主固有免疫之間相互關(guān)系的認識,。（生物谷Bioon.com）
生物谷推薦原味出處：
Journal of Virology doi:10.1128/JVI.00733-11
Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65
Xiaofan Li, Deguang Liang, Xianzhi Lin, Erle S. Robertson, and Ke Lan
Latency-associated nuclear antigen (LANA)-1 of Kaposi's sarcoma-associated herpesvirus (KSHV) is the major viral latent protein and functions as a multifaceted protein. Here, we report that LANA-1 attenuates endothelial response to tumor necrosis factor (TNF)-α stimulation and inhibits consequent neutrophil chemotaxis. Reporter assay showed that LANA-1 constantly repressed nuclear factor (NF)-B transactivity upon TNF-α stimulation. We also found that LANA-1 decreased nuclear p65 protein level through enhancement of poly-ubiquitylation-mediated p65 degradation, and an ElonginB/C-Cullin5-LANA-1-p65 complex assembled by LANA-1 was responsible for this enhanced p65 degradation. In telomerase-immortalized human umbilical vein endothelial cells, LANA-1 was demonstrated to repress interleukin-8 expression, which was involved in neutrophil recruitment to the inflammatory site. Through an in vitro transmigration assay, we determined a suppressive effect of LANA-1 on neutrophil chemotaxis. Our work suggests that KSHV LANA-1 is a negative modulator of acute inflammation, and shed light on a new mechanism by which latently infected KSHV evades the host innate immune response.
