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Typhoid toxin hijacks Wnt5a to potentiate TGFβ-mediated senescence and Salmonella infection

ABSTRACT: 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 enterica hijacks 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Mark Collins

LAB HEAD: Mark Collins

PROVIDER: PXD037373 | Pride | 2023-09-07

REPOSITORIES: Pride

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			Action	DRS
	OT_190415_MElGazaly_HQ_R1-01.raw	Raw
	OT_190415_MElGazaly_HQ_R2-01.raw	Raw
	OT_190415_MElGazaly_HQ_R3-01.raw	Raw
	OT_190415_MElGazaly_HQ_R4-01.raw	Raw
	OT_190415_MElGazaly_TT_R1-01.raw	Raw

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