Molecular insights into the targeting of proteins to the inner nuclear membrane

我们的器官和组织的正常运作与组成它们的细胞有着内在的联系。同样，这些细胞的顺利运作部分依赖于正确的细胞区室内蛋白质的正确分配。例如，参与基因调控的蛋白质被定位到细胞核，也就是染色体的所在。这通常是通过核膜上的孔来实现的，这些孔专门进口含有独特邮政编码的蛋白质，即给定的氨基酸序列。对于可溶性蛋白来说，这一过程相对来说已经很好理解了。对于整合在细胞核包膜中的蛋白质，一种新的靶向信号直到最近才被发现。然而，这种进口的机制仍然是个谜。由于所有病毒都是依赖细胞功能繁殖的强制性寄生虫，而且是比我们简单得多的生物体，因此它们构成了研究细胞的极好模型。我们最近的研究表明，单纯疱疹病毒1型基因组编码的特定病毒蛋白的核膜靶向并不遵循经典规则。与任何细胞蛋白不同，这种蛋白也可以在细胞的其他地方和成熟病毒上找到。这种蛋白质给我们提供了一个非常独特的机会来探索核靶向。从长远来看，目前的研究计划将研究核靶向机制是否具有普遍性，它是如何被调节的，以及病毒是否可以调节甚至垄断它。这个研究计划将在未来的十年或二十年阐明这个非常复杂的生物机制。

The proper functioning of our organs and tissues is intrinsically linked to the cells that compose them. Similarly, the smooth operation of these cells is in part dependent on the correct partitioning of proteins within the right cellular compartments. For instance, proteins involved in the regulation of our genes are targeted to the nucleus, where our chromosomes are found. This is typically achieved via pores in the nuclear envelope that specifically import proteins containing a unique postal code, i.e. a given sequence of amino acids. This process is relatively well understood for soluble proteins. For proteins that are integrated in the envelope of the nucleus, a novel targeting signal has only recently been found. However, the mechanism for that import remains is still enigmatic. Since all viruses are obligatory parasites that rely on cellular functions to multiply and much simpler organisms than us, they constitute excellent models to study cells. We have recently shown that the targeting to the nuclear envelope of a particular viral protein encoded by the herpes simplex virus type 1 genome does not follow the classical rules. Unlike any cellular proteins, this protein can also be found elsewhere in the cells and onto mature viruses. This protein gives us a very unique opportunity to probe nuclear targeting. In the long run, the present research program will examine whether the nuclear targeting machinery is universal, how it is regulated and whether viruses can modulate or perhaps even monopolize it. This research program should over the next decade or two elucidate this very complex biological machinery.