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

我们器官和组织的正常功能与组成它们的细胞有着内在的联系。类似地，这些细胞的平稳运行部分取决于正确的细胞区室中蛋白质的正确分配。例如，参与基因调控的蛋白质被定位在染色体所在的细胞核中，这通常是通过核膜上的孔来实现的，这些孔专门输入含有独特邮政编码的蛋白质，即给定的氨基酸序列。对于可溶性蛋白质，该过程相对较好地理解。对于整合在核被膜中的蛋白质，一种新的靶向信号直到最近才被发现，然而，这种输入的机制仍然是个谜。由于所有病毒都是依赖细胞功能繁殖的寄生虫，而且比我们简单得多，因此它们构成了研究细胞的绝佳模型。我们最近已经表明，由单纯疱疹病毒1型基因组编码的特定病毒蛋白的核膜靶向不遵循经典规则。与任何细胞蛋白质不同，这种蛋白质也可以在细胞的其他地方和成熟病毒上找到。这种蛋白质给了我们一个非常独特的机会来探测核靶向。从长远来看，目前的研究计划将研究核靶向机制是否是普遍的，它是如何被调节的，以及病毒是否可以调节甚至垄断它，这项研究计划将在未来十年或二十年内阐明这一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.