人类免疫缺陷病毒1型(HIV-1)的基因组除了能够编码病毒结构蛋白外，还能表达额外的增强病毒基因表达、病毒传染性及病毒颗粒产量的蛋白。
Vpu是一个16kDa的膜蛋白，是由包膜前体mRNA编码，它表达于病毒生产的晚期并通过膜孔的形成增强艾滋病毒的复制，也能够促进HIV-1感染的人类T淋巴细胞的凋亡。Vpu的一些功能依赖于它与泛素蛋白酶体蛋白降解系统的相互作用，但是由于它促进凋亡的机制复杂，目前还不甚明确。
为此，法国凡尔赛大学的研究人员利用果蝇模型来研究体内Vpu的功能。实验发现，在果蝇翅膀发育过程中Vpu的表达会导致组织丢失，这可能是通过caspase（含半胱氨酸的天冬氨酸蛋白水解酶）介导了细胞凋亡。此外，Vpu引起凋亡基因reaper的表达，下调了凋亡蛋白(IAPs)的抑制物（抗caspase E3泛素连接酶）。事实上，Vpu同时也减少了果蝇IAP1（果蝇凋亡调控因子，DIAP1)的累积。
研究结果阐明了IAP1 Vpu与SLIMB/β-TrCP蛋白物理上的相互作用。与哺乳动物一样，SLIMB/βTrCP依赖的或者是非依赖的Vpu作用都在果蝇翅膀中被观察到。
通过失活c-Jun氨基末端激酶(JNK)通路，这些组织中Vpu的促凋亡作用可以被终止。此次研究表明，Vpu通过激活保守的JNK通路促进了细胞凋亡，这也是第一次提供功能学证据证明了这个结论。相关论文发表在3月29日的美国《公共科学图书馆·综合》（PLoS One）上。（生物谷Deepblue编译）
doi: 10.1371/journal.pone.0034310
PMC:
PMID:
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.
