The σR regulon of Streptomyces coelicolor A3(2) reveals a key role in protein quality control during disulphide stress
The σR regulon of Streptomyces coelicolor A3(2) reveals a key role in protein quality control during disulphide stress
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DOI：
10.1099/mic.0.037804-0
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发表时间：
2010-06-01
期刊：
影响因子：
2.8
通讯作者：
Paget, Mark S. B.
中科院分区：
文献类型：
--
作者：
Kallifidas, Dimitris;Thomas, Derek;Paget, Mark S. B.
二酰胺是一种人工二硫化物生成亲电体，模拟细胞硫醇二硫化物氧化还原状态（二硫化物应激）的氧化转变。革兰氏阳性细菌天蓝色链霉菌通过sigma（R）-RsrA系统感测并响应二硫化物胁迫，该系统包含细胞质外功能（ECF）sigma因子和氧化还原活性抗sigma因子。帮助保护和从二硫化物应激中恢复的已知靶标包括硫氧还蛋白系统和参与产生主要硫醇缓冲剂真菌硫醇的基因。在这里，我们确定了野生型和sigR突变背景下对二酰胺的整体反应，以了解sigma（R）在这种反应中的作用，并揭示了允许细胞科普二硫化物应激的其他调控途径。除了巯基氧化，二酰胺被发现会导致蛋白质错误折叠和聚集，从而引起HspR热休克调节子的诱导。虽然这种反应是sigma（R）-独立的，但sigma（R）确实直接控制Clp和Lon ATP依赖性AAA（+）蛋白酶，这可以部分解释sigR突变体重新溶解蛋白质聚集体的能力降低。σ还控制msrA和msrB甲硫氨酸亚砜还原酶基因，这意味着σ-RsrA负责在氧化应激期间维持半胱氨酸和甲硫氨酸残基。这项工作表明，sigma（R）-RsrA系统在蛋白质质量控制中起着比以前认识到的更重要的作用，并强调了控制细胞硫醇-二硫化物氧化还原平衡的重要性。
Diamide is an artificial disulphide-generating electrophile that mimics an oxidative shift in the cellular thiol disulphide redox state (disulphide stress). The Gram-positive bacterium Streptomyces coelicolor senses and responds to disulphide stress through the sigma(R)-RsrA system, which comprises an extracytoplasmic function (ECF) sigma factor and a redox-active anti-sigma factor. Known targets that aid in the protection and recovery from disulphide stress include the thioredoxin system and genes involved in producing the major thiol buffer mycothiol. Here we determine the global response to diamide in wild-type and sigR mutant backgrounds to understand the role of sigma(R) in this response and to reveal additional regulatory pathways that allow cells to cope with disulphide stress. In addition to thiol oxidation, diamide was found to cause protein misfolding and aggregation, which elicited the induction of the HspR heat-shock regulon. Although this response is sigma(R)-independent, sigma(R) does directly control Clp and Lon ATP-dependent AAA(+) proteases, which may partly explain the reduced ability of a sigR mutant to resolubilize protein aggregates. sigma(R) also controls msrA and msrB methionine sulphoxide reductase genes, implying that sigma(R)-RsrA is responsible for the maintenance of both cysteine and methionine residues during oxidative stress. This work shows that the sigma(R)-RsrA system plays a more significant role in protein quality control than previously realized, and emphasizes the importance of controlling the cellular thiol-disulphide redox balance.