Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties.
Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties.
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DOI：
10.1073/pnas.1815660115
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发表时间：
2018-12-18
影响因子：
11.1
通讯作者：
Gallo RC
中科院分区：
文献类型：
--
作者：
Zella D;Curreli S;Benedetti F;Krishnan S;Cocchi F;Latinovic OS;Denaro F;Romerio F;Djavani M;Charurat ME;Bryant JL;Tettelin H;Gallo RC
我们提供的证据表明：（i）支原体菌株在体内小鼠模型中促进淋巴瘤的发生;（ii）细菌伴侣蛋白DnaK可能通过干扰与DNA损伤控制/修复和细胞周期/凋亡相关的重要途径而参与转化过程和对抗癌药物的耐药性;（iii）在感染小鼠的某些肿瘤中发现了非常低拷贝数的支原体DnaK DNA序列。其他肿瘤相关细菌携带类似的DnaK蛋白。我们的数据表明，一个共同的机制，即细菌可以参与细胞转化和抗癌药物的耐药性的打和隐藏/运行机制。我们分离出一株促进SCID小鼠淋巴瘤发生的人支原体，指出p53依赖性机制与未感染p53−/− SCID小鼠的淋巴瘤发生相似。此外，体外支原体感染降低p53活性。支原体感染细胞中p53的免疫沉淀鉴定了几种支原体蛋白，包括DnaK，Hsp 70分子伴侣家族的一员。我们专注于DnaK，因为它能够与蛋白质相互作用。我们证明，支原体DnaK与参与关键细胞途径的人类蛋白质相互作用并降低其活性，包括DNA-PK和PARP 1，这些蛋白质是有效DNA修复所需的，并与USP 10（一种关键的p53调节剂）结合，损害p53依赖性抗癌功能。这也降低了依赖p53发挥作用的抗癌药物的疗效。在感染的小鼠中早期检测到支原体，但在一些原发性和继发性肿瘤中仅发现低拷贝数的支原体DnaK DNA序列，表明转化的打了就跑/隐藏机制。未感染的旁观者细胞采取了外源性DnaK，提示可能的旁分泌功能，在促进恶性转化，以上细胞感染支原体。系统发生氨基酸分析表明，与人类癌症相关的其他细菌具有类似的DnaKs，这与通过破坏DNA修复机制介导的细胞转化的常见机制以及p53失调一致，这也导致癌症耐药性。这表明某些细菌的致癌特性是DnaK介导的。
We provide evidence here that (i) a strain of mycoplasma promotes lymphomagenesis in an in vivo mouse model; (ii) a bacterial chaperone protein, DnaK, is likely implicated in the transformation process and resistance to anticancer drugs by interfering with important pathways related to both DNA-damage control/repair and cell-cycle/apoptosis; and (iii) a very low copy number of DNA sequences of mycoplasma DnaK were found in some tumors of the infected mice. Other tumor-associated bacteria carry a similar DnaK protein. Our data suggest a common mechanism whereby bacteria can be involved in cellular transformation and resistance to anticancer drugs by a hit-and-hide/run mechanism. We isolated a strain of human mycoplasma that promotes lymphomagenesis in SCID mice, pointing to a p53-dependent mechanism similar to lymphomagenesis in uninfected p53−/− SCID mice. Additionally, mycoplasma infection in vitro reduces p53 activity. Immunoprecipitation of p53 in mycoplasma-infected cells identified several mycoplasma proteins, including DnaK, a member of the Hsp70 chaperon family. We focused on DnaK because of its ability to interact with proteins. We demonstrate that mycoplasma DnaK interacts with and reduces the activities of human proteins involved in critical cellular pathways, including DNA-PK and PARP1, which are required for efficient DNA repair, and binds to USP10 (a key p53 regulator), impairing p53-dependent anticancer functions. This also reduced the efficacy of anticancer drugs that depend on p53 to exert their effect. mycoplasma was detected early in the infected mice, but only low copy numbers of mycoplasma DnaK DNA sequences were found in some primary and secondary tumors, pointing toward a hit-and-run/hide mechanism of transformation. Uninfected bystander cells took up exogenous DnaK, suggesting a possible paracrine function in promoting malignant transformation, over and above cells infected with the mycoplasma. Phylogenetic amino acid analysis shows that other bacteria associated with human cancers have similar DnaKs, consistent with a common mechanism of cellular transformation mediated through disruption of DNA-repair mechanisms, as well as p53 dysregulation, that also results in cancer-drug resistance. This suggests that the oncogenic properties of certain bacteria are DnaK-mediated.
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影响因子：
6.4
作者：
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通讯作者：
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作者：
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通讯作者：
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