A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism
A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism
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DOI：
10.1038/nature06782
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发表时间：
2008-04-10
期刊：
影响因子：
64.8
通讯作者：
Dudler, Robert
中科院分区：
文献类型：
--
作者：
Groll, Michael;Schellenberg, Barbara;Dudler, Robert
致病菌经常使用效应分子来增加毒力。在大多数情况下，效应器的作用方式仍然是未知的。丁香假单胞菌的研究。在植物中，丁香科（Pss）分泌丁香素A (SylA)，这是一种混合的非核糖体肽/聚酮合成酶的产物(1)。在这里，我们确定SylA是一个毒力因子，因为通过基因破坏获得的Pss菌株B728a的SylA阴性突变体对其宿主菜豆的毒力明显降低。我们发现SylA不可逆地抑制真核生物蛋白酶体的所有三种催化活性，从而将蛋白酶体抑制添加到毒力因子的作用模式中。酵母蛋白酶体与SylA复合物的晶体结构揭示了一种新的与催化亚基共价结合的机制。因此，SylA定义了一类新的蛋白酶体抑制剂，其中包括glidobactin a (GlbA)，这是一种结构相关的化合物，来自一种未知的Burkholderiales目(2)，我们证明了类似的蛋白酶体抑制机制。由于蛋白酶体抑制剂是一类很有前途的抗肿瘤药物，一种新的抑制性天然产物家族的发现，我们称之为sybactin，也可能对抗癌药物的开发产生影响(3)。SylA和GlbA合成酶基因的同源物在其他一些致病菌中也被发现，包括人类病原体假假麦氏伯克氏菌，它是类鼻疽病的病原体(4)。因此，这些细菌可能能够产生sybalactin类蛋白酶体抑制剂。
Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. Strains of Pseudomonas syringae pv. syringae (Pss) secrete syringolin A (SylA), a product of a mixed non-ribosomal peptide/polyketide synthetase, in planta(1). Here we identify SylA as a virulence factor because a SylA-negative mutant in Pss strain B728a obtained by gene disruption was markedly less virulent on its host, Phaseolus vulgaris (bean). We show that SylA irreversibly inhibits all three catalytic activities of eukaryotic proteasomes, thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. The crystal structure of the yeast proteasome in complex with SylA revealed a novel mechanism of covalent binding to the catalytic subunits. Thus, SylA defines a new class of proteasome inhibitors that includes glidobactin A (GlbA), a structurally related compound from an unknown species of the order Burkholderiales(2), for which we demonstrate a similar proteasome inhibition mechanism. As proteasome inhibitors are a promising class of anti-tumour agents, the discovery of a novel family of inhibitory natural products, which we refer to as syrbactins, may also have implications for the development of anti-cancer drugs(3). Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis(4). It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.