Typhoid toxin hijacks Wnt5a to potentiate TGFß-mediated senescence and Salmonella infections
Typhoid toxin hijacks Wnt5a to potentiate TGFß-mediated senescence and Salmonella infections
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伤寒毒素劫持 Wnt5a 增强 TGFα 介导的衰老和沙门氏菌感染
DOI：
10.1101/2022.10.05.510870
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
ElGhazaly M
中科院分区：
文献类型：
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作者：
ElGhazaly M
我们基因组的损伤导致哺乳动物细胞急性衰老，这些细胞经历生长停滞并释放分泌组，通过衰老相关分泌表型（SASP）在旁观者细胞中引发细胞周期停滞。因此，急性衰老是一种强大的肿瘤抑制因子。沙门氏菌通过其伤寒毒素劫持衰老，这种毒素篡夺了衰老细胞应激分泌组中未知的因子，介导细胞内感染。在这里，毒素诱导的衰老细胞（txSCs）的转录组学及其分泌组学的蛋白质组学鉴定了通过SMAD转录因子激活tgf - β途径的分泌配体。配体Wnt5a建立了一个自我放大的正反馈回路，驱动tgf - β信号传导，通过激活ddr，促进txSCs的自分泌衰老和幼稚旁观者细胞的旁分泌衰老。Wnt5a和GDF15增加了宿主细胞对感染的易感性。这项研究揭示了一种细菌病原体是如何利用一种天生的抗癌防御来引起广泛的损害和介导感染的。
Damage to our genome causes acute senescence in mammalian cells, which undergo growth arrest and release a secretome that elicits cell cycle arrest in bystander cells through the senescence-associated secretory phenotype (SASP). Thus, acute senescence is a powerful tumour suppressor.Salmonella entericahijacks senescence through its typhoid toxin, which usurps unidentified factors in the stress secretome of senescent cells to mediate intracellular infections. Here, transcriptomics of toxin-induced senescent cells (txSCs) and proteomics of their secretome identified secreted ligands that activate the TGFβ pathway through SMAD transcription factors. The ligand Wnt5a established a self-amplifying positive feedback loop driving TGFβ signalling, which enforced autocrine senescence in txSCs and paracrine senescence in naive bystander cells by activation of DDRs. Wnt5a and GDF15 increased host cell susceptibility to infection. The study reveals how an innate defence against cancer is co-opted by a bacterial pathogen to cause widespread damage and mediate infections.