Pleiotropic roles of Clostridium difficile sin locus.
Pleiotropic roles of Clostridium difficile sin locus.
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DOI：
10.1371/journal.ppat.1006940
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发表时间：
2018-03
期刊：
影响因子：
6.7
通讯作者：
Govind R
中科院分区：
文献类型：
--
作者：
Girinathan BP;Ou J;Dupuy B;Govind R
艰难梭菌是引起医院内腹泻和伪膜性结肠炎的主要原因。它产生休眠的孢子，作为一种传染性媒介，负责传播疾病和保持生物体在环境中的持久性。在枯草芽孢杆菌中，编码SinR(113个氨基酸)和SINI(57个氨基酸)的SIN基因座负责抑制产孢量。在枯草芽孢杆菌中，SinR主要作为其靶基因的抑制子来控制孢子形成、生物膜形成和自溶。SINI是SINR的抑制剂，二者的相互作用决定了SINR能否抑制其靶基因的表达。艰难梭菌基因组在操纵子中携带两个sinR同源物，我们将其命名为sinR和sinR‘，分别编码SinR(112aa)和sinR’(105aa)。在本研究中，我们构建并鉴定了艰难梭菌R20291和JIR8094两个不同菌株的SIN基因座突变体，以破译该基因座在艰难梭菌生理中的作用。对sinRR‘突变体的转录组分析表明，它们在艰难梭菌中控制包括产孢子、毒素产生和运动在内的几个途径具有多效性作用。通过各种遗传和生化实验，我们已经证明SinR可以调节这些途径中关键调控因子的转录，包括sigD、sp0A和Cody。我们发现，SinR‘通过阻断SinR的抑制活性而起到拮抗SinR的作用。使用仓鼠模型，我们还证明了SIN基因是艰难梭菌成功感染所必需的。这项研究揭示了SIN基因座是连接产孢子、毒素产生和运动的基因调控网络的中心纽带，这三个关键途径对艰难梭菌的发病至关重要。在枯草芽孢杆菌中，芽胞形成、竞争能力和生物膜的形成受一种称为SinR的多效性调节因子的调节。艰难梭菌基因组中存在两个sinR同源物作为操纵子，此后被标记为sinR和sinR‘。我们的详细研究表明，在艰难梭菌中，SinR和SinR‘是调控包括产孢子、毒素产生和运动在内的几个途径所需的关键主控调控因子。
Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR’, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus’s role in C. difficile physiology. Transcriptome analysis of the sinRR’ mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. In Bacillus subtilis, sporulation, competence and biofilm formation are regulated by a pleiotropic regulator called SinR. Two sinR homologs are present in C. difficile genome as an operon and henceforth labeled as sinR and sinR’. Our detailed investigation revealed that in C. difficile, the SinR and SinR’ are key master regulators needed for the regulation of several pathways including sporulation, toxin production, and motility.
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3.7
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