人類(lèi)免疫缺陷病毒1型(HIV-1)的基因組除了能夠編碼病毒結(jié)構(gòu)蛋白外,，還能表達(dá)額外的增強(qiáng)病毒基因表達(dá)、病毒傳染性及病毒顆粒產(chǎn)量的蛋白,。
Vpu是一個(gè)16kDa的膜蛋白,，是由包膜前體mRNA編碼，它表達(dá)于病毒生產(chǎn)的晚期并通過(guò)膜孔的形成增強(qiáng)艾滋病毒的復(fù)制,，也能夠促進(jìn)HIV-1感染的人類(lèi)T淋巴細(xì)胞的凋亡,。Vpu的一些功能依賴(lài)于它與泛素蛋白酶體蛋白降解系統(tǒng)的相互作用，但是由于它促進(jìn)凋亡的機(jī)制復(fù)雜,，目前還不甚明確,。
為此,，法國(guó)凡爾賽大學(xué)的研究人員利用果蠅模型來(lái)研究體內(nèi)Vpu的功能。實(shí)驗(yàn)發(fā)現(xiàn),，在果蠅翅膀發(fā)育過(guò)程中Vpu的表達(dá)會(huì)導(dǎo)致組織丟失,，這可能是通過(guò)caspase（含半胱氨酸的天冬氨酸蛋白水解酶）介導(dǎo)了細(xì)胞凋亡。此外,，Vpu引起凋亡基因reaper的表達(dá),，下調(diào)了凋亡蛋白(IAPs)的抑制物（抗caspase E3泛素連接酶）。事實(shí)上,，Vpu同時(shí)也減少了果蠅IAP1（果蠅凋亡調(diào)控因子,，DIAP1)的累積。
研究結(jié)果闡明了IAP1 Vpu與SLIMB/β-TrCP蛋白物理上的相互作用,。與哺乳動(dòng)物一樣,，SLIMB/βTrCP依賴(lài)的或者是非依賴(lài)的Vpu作用都在果蠅翅膀中被觀察到。
通過(guò)失活c-Jun氨基末端激酶(JNK)通路,，這些組織中Vpu的促凋亡作用可以被終止,。此次研究表明，Vpu通過(guò)激活保守的JNK通路促進(jìn)了細(xì)胞凋亡,，這也是第一次提供功能學(xué)證據(jù)證明了這個(gè)結(jié)論,。相關(guān)論文發(fā)表在3月29日的美國(guó)《公共科學(xué)圖書(shū)館·綜合》（PLoS One）上。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.0034310
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The HIV-1 Vpu Protein Induces Apoptosis in Drosophila via Activation of JNK Signaling
Christelle Marchal, Gérald Vinatier, Matthieu Sanial, Anne Plessis, Anne-Marie Pret, Bernadette Limbourg-Bouchon, Laurent Théodore, Sophie Netterl.
The genome of the human immunodeficiency virus type 1 (HIV-1) encodes the canonical retroviral proteins, as well as additional accessory proteins that enhance the expression of viral genes, the infectivity of the virus and the production of virions.The accessory Viral Protein U (Vpu), in particular, enhances viral particle production, while also promoting apoptosis of HIV-infected human T lymphocytes. Some Vpu effects rely on its interaction with the ubiquitin–proteasome protein degradation system, but the mechanisms responsible for its pro-apoptotic effects in vivo are complex and remain largely to be elucidated.We took advantage of the Drosophila model to study the effects of Vpu activity in vivo. Expression of Vpu in the developing Drosophila wing provoked tissue loss due to caspase-dependent apoptosis. Moreover, Vpu induced expression of the pro-apoptotic gene reaper, known to down-regulate Inhibitor of Apoptosis Proteins (IAPs) which are caspase-antagonizing E3 ubiquitin ligases. Indeed, Vpu also reduced accumulation of Drosophila IAP1 (DIAP1).Though our results demonstrate a physical interaction between Vpu and the proteasome-addressing SLIMB/β-TrCP protein, as in mammals, both SLIMB/βTrCP-dependent and -independent Vpu effects were observed in the Drosophila wing.Lastly, the pro-apoptotic effect of Vpu in this tissue was abrogated upon inactivation of the c-Jun N-terminal Kinase (JNK) pathway. Our results in the fly thus provide the first functional evidence linking Vpu pro-apoptotic effects to activation of the conserved JNK pathway.
