细胞生物学论文翻译作业

细胞生物学论文翻译作业湖北师范学院生物系0701班 岑翔2007114010107翻译：NATURE|Vol 459|18 June 2009疟疾被揭示的门控者Sarah B. Reiff and Boris Striepen疟原虫用以将其蛋白质库输出至宿主细胞的一种分子已经被识别，这提供给研究人员以治疗学上具有无限潜在价值的目标。疟疾是一种破坏性的传染病，据称其每年会夺取大约1万人的生命。最严重的形式是由一种被称之为恶性疟原虫（或镰状疟原虫）的单细胞寄生虫引起的，这是一种让人们不断尝试去根除却又屡屡失败的可怕敌人。恶性疟原虫具有很多生存技巧：它不断地改变呈交予宿主的表面蛋白质（注1），从而使宿主的免疫系统变得混乱，并且会迅速提高对药物的抵抗性（注2）。在这个问题上，de Koning-Ward和他的同事（注3）弄清了这个以及另外一种寄生虫所具有的令人不安的本领，一种将自身所拥有的成百上千的蛋白质注入宿主体内的能力。 一支寄生虫蛋白构成的军队对宿主细胞的入侵也许就是恶性疟原虫能在细胞中存活并发展到其他几种病原体能够设法征服红血球（RBC）的原因。红血球以及微孔荒漠（cellular deserts？）高效化地追求氧的运输这样一个简单的目的，缺乏大量通常能够被细胞内病原体利用的结构，如细胞核和膜泡运输系统。恶性疟原虫面对着广泛重塑红细胞的挑战，而寄生虫的感染蛋白质也许就是这种改变的中介者。其中的一项改变就是在红血球表面像分子魔术贴一样的旋钮构造，这导致了被感染的细胞粘附在毛细血管内层（注4）。通过藏身于循环系统外围的方式，被感染的细胞似乎在避免在脾脏中被消除。宿主的结果非常悲惨-大量被感染的红血球在大脑和肾的毛细血管的积累会导致器官最终死亡。 恶性疟原虫用以将其蛋白质输出至红血球细胞质的机制曾被疟疾研究者狂热地追求。了解这一过程能帮助发展阻止寄生虫生长或限制严重疾病的介入手段。恶性疟原虫居住在红血球液胞内部并且需要在将蛋白质输出到目的地的过程中跨越几道生理性阻碍。这些阻碍包括寄生虫膜，液胞膜，以及对于很多蛋白质来说还有红血球膜。蛋白质由寄生虫运往液胞空间的这种典型分泌路线存在于所有真核细胞中（具有细胞核和膜结构细胞器的细胞）。但是蛋白质如何穿过液胞膜仍然是个迷。对于一种特殊的“输出地址标签”的鉴定（注5，6）（疟原虫属蛋白质基元序列的氨基末端导致了它们从液胞中输出）是一个重大进展并使得作者得出了他们当前的假设（注3）。他们假定红血球液胞膜上有一个“门控者”能读取输出标签并把蛋白质传递到红血球细胞质中，他们进一步假定那个“门控者”是由被他们称之为疟原虫属易位子输出蛋白（PTEX）的寄生虫蛋白质构成的复合体。 为了找到液胞膜运输蛋白存在的的证据，de Koning-Ward和他的同事（注3）总结出一个潜在的PTEX构成要素的所需特征清单：必须是当前在血液阶段中的寄生虫，必须是对寄生虫在红血球中生长所必不可少的，被寄生虫所分泌，并且与液胞膜联系在一起。使用这些标准和一系列的生物信息学、遗传学以及生物化学手段，他们将候选范围从数百种寄生虫蛋白减小到两种，分别叫做HSP101和PTEX150。HSP101是一种属于AAA+级ATPases（ATP泵）超家族的酶，并且有能力将ATP提供给蛋白质传输作为动力能源。PTEX150是一种新鉴定的能与HSP101相互作用的寄生虫蛋白，符合构成PTEX潜在结构的特征。生物化学实验额外鉴别出三种近似的PTEX组分。其中，EXP2非常有趣，由于它是一种积分膜蛋白，所以可以停在PTEX复合体和液胞膜上并作为一种孔潜在发挥作用。 所以de Koning-Ward和他的同事（注3）似乎已经鉴定出PTEX允许其发挥“门控者”作用的所需组成结构。但是PTEX真的运输蛋白质么？坐着令人信服地展示了这受到货物蛋白的影响，重要的是，这仅仅在蛋白质携带出口地址标签时才成立，这也与之前假设的功能是相一致的。PTEX假设不是唯一一个假设出来用于解释疟疾蛋白质输出的模型，另外一些人提出一种基于液胞运输小泡的萌芽的模型（注7），这些小泡被预测为在被感染的细胞中将转化为膜结构并被称之为毛雷尔氏小点。也许这几套不同的尤其是在命运和物理性质上都各不相同的蛋白质需要不同的机器去找到它们的目标位置。 第三种潜在的模型在卵菌研究中被提出。他们培养一种看起来像真菌的病原体，但实际在进化角度上与疟原虫关系紧密，而且他们同样把蛋白质输出到宿主细胞内。有趣的是，这些蛋白质在卵菌与疟原虫属彼此的输出转运中相互分享、相互交换疟原虫属出口地址标签（注8，9）。卵菌研究者有两个额外发现：他们注意到地址标签同样在宿主蛋白质中被发现，而且这些运输标签的蛋白质还能在缺少病原体的情况下进入宿主细胞（注10，11）。这可能表明，这些病原体颠覆了运输元素自然存在于宿主细胞膜的结论。 研究被认为是涉及到这些模型的不同版本的重要对象将提供关键性的见解。比如，缺失基因编码PTEX复合物的成分将会溶解蛋白出口并提供关于PTEX结构的确切证据。导致疟原虫突变的技术障碍也于近期被排除（注12），当前的论文（注3）提供了一个关于PTEX功能的强有力的机械模型，并且非常关键地识别了一系列将在未来被得以确认的优良的候选基因。Sarah B. Reiff and Boris Striepen are at the Centerfor Tropical and Emerging Global Diseases, andthe Department of Cellular Biology, University ofGeorgia, Athens, Georgia 30602, USA.e-mail: 1. Scherf, A., Lopez-Rubio, J. J. & Riviere, L. Annu. Rev.Microbiol. 62, 445470 (2008).2. Baird, J. K. N. Engl. J. Med. 352, 15651577 (2005).3. de Koning-Ward, T. F. et al. Nature 459, 945949 (2009).4. Crabb, B. S. et al. Cell 89, 287296 (1997).5. Marti, M. et al. Science 306, 19301933 (2004).6. Hiller, N. L. et al. Science 306, 19341937 (2004).7. Bhattacharjee, S. et al. Blood 111, 24182426 (2008).8. Bhattacharjee, S. et al. PLoS Pathog. 2, e50 (2006).9. Grouffaud, S. et al. Microbiology 154, 37433751 (2008).10. Birch, P. R. et al. Curr. Opin. Plant Biol. 11, 373379 (2008).11. Dou, D. et al. Plant Cell 20, 19301947 (2008).12. Combe, A. et al. Cell Host Microbe 5, 386396 (2009).原文：MALARIAThe gatekeeper revealedSarah B. Reiff and Boris StriepenA molecular machine used by the malaria parasite to export its protein armoury into the host cell has at last been identified, providing researchers with a potentially invaluable therapeutic target.Malaria is a devastating infectious diseasethat claims around one million lives each year.The most severe form is caused by a unicellularparasite called Plasmodium falciparum a formidable foe that has repeatedly frustratedattempts to eradicate it. P. falciparumhas many survival tricks: it constantly variesthe surface proteins presented to the host1,thereby confounding the host immune system,and it rapidly develops resistance to drugs2.In this issue (page 945), de Koning-Ward andcolleagues3 get to the bottom of yet anotherof the parasites unsettling talents, theability to inject hundreds of its ownproteins into the host cell.The invasion of the host cell by anarmy of parasite proteins is probablyone reason why P. falciparumcan survive and develop in a cell thatfew other pathogens have managedto conquer, the red blood cell (RBC).Streamlined for a single purpose thetransport of oxygen RBCs are cellulardeserts, lacking many of the amenitiesusually enjoyed by intracellular pathogens,such as a nucleus and a vesicular transportsystem. P. falciparum masters this challengeby extensive remodelling of the RBC, and theparasites injected proteins are probably theagents of these changes. One such change isthe formation of knobs on the RBC surface thatbehave like molecular Velcro, resulting in adhesionof infected cells to the lining of capillaryblood vessels4. By hiding out in the peripheryof the circulatory system in this way, infectedcells seem to avoid elimination in the spleen.The consequences for the host are dire themassive accumulation of infected RBCs in thecapillary beds of the brain and kidney can leadto organ failure and ultimately death.The mechanism used by P. falciparum toexport proteins to the RBC cytoplasm hasbeen hotly pursued by malaria researchers.Understanding this process could aid thedevelopment of interventions that block theparasites growth or limit the severity of thedisease. In the RBC, P. falciparum residesinside a vacuole, and exported proteins mustovercome several physical barriers en route totheir destinations. These barriers include theparasite membrane, the vacuole membraneand, for some proteins, the RBC membrane.Proteins exported from the parasite into thevacuolar space follow the typical secretionpathway that exists in all eukaryotic cells(cells with a nucleus and membrane-boundorganelles). But how these proteins crossthe vacuole membrane has remained a mystery.The identification5,6 of a specific exportaddress tag a sequence motif at the aminoterminus of Plasmodium proteins that results intheir export out of the vacuole was a majoradvance, and led the authors to their currenthypothesis3. They propose that there is a gatekeeperin the vacuole membrane that readsthe export tag and delivers proteins from thevacuole into the RBC cytoplasm (Fig. 1). Theyfurther assume that the gatekeeper is madeup of a complex of parasite proteins that theycall the Plasmodium translocon of exportedproteins (PTEX).To find evidence of a vacuolar membraneprotein transporter, de Koning-Ward andcolleagues3 assembled a list of required characteristicsof potential PTEX components: theyshould be present in the blood-stage parasite,be essential for parasite growth in RBCs, besecreted from the parasite, and associate withthe vacuole membrane. Using these criteriaand a battery of bioinformatics, genetic andbiochemical approaches, they narrowed thefield from hundreds of candidates to two parasiteproteins, called HSP101 and PTEX150.HSP101 is an enzyme belonging to the AAA+superfamily of ATPases, and would be able topower protein export using ATP as an energysource. PTEX150 is a newly identified parasiteprotein that interacts with HSP101, a featureconsistent with its being a potential componentof the PTEX. Biochemical experimentsidentified an additional three likely PTEXcomponents. Among these, EXP2 is particularlyinteresting, as it is an integral membraneprotein and could therefore anchor the PTEXcomplex to the vacuole membrane andpotentially function as a pore.So de Koning-Ward and colleagues3 seemto have identified the necessary componentsfor the PTEX that would allow it to functionas a gatekeeper. But does the PTEX actuallyexport proteins? The authors show convincinglythat it interacts with cargo proteins and,importantly, does so only if the protein carriesthe export address tag, which is consistent withits proposed function.The PTEX hypothesis is not the only modelproposed to explain malaria protein export.Another suggested model7 is based on thebudding of transport vesicles from the vacuole.These vesicles are then predicted to transforminto membranous structures in the infectedcell known as Maurers clefts. Its possible thatdifferent sets of proteins, especially thosewith different destinies or physical properties,require different machinery to reach theirtarget locations.A third potential model arises from studieson oomycetes. These plant pathogens look likefungi, but are actually evolutionarily relatedto malaria parasites and also export proteinsinto the cells of their hosts. Intriguingly, theseproteins share the Plasmodium export addresstag, and swapping tags between oomycetesand Plasmodium results in export in bothcases8,9. Oomycete researchers have made twoadditional observations: they noted that theaddress tag is also found on host proteins, andthat proteins carrying the tag can gain entry tohost cells in the absence of the pathogen10,11.This might suggest that the pathogens are subvertingtransport elements naturally present inhost membranes.Studying mutated versions of any of thecentral players thought to be involved in thesemodels would provide crucial insights. Forinstance, deletion of the genes encoding thecomponents of the PTEX complex shouldablate protein export and provide conclusiveproof of the PTEX mechanism. Someof the technical obstacles to generating suchmutants in the malaria parasite have recentlybeen removed12. The current paper3 providesa strong mechanistic model of PTEX functionand, crucially, identifies a list of excellentcandidate genes to be valid