ABSTRACT Typhoid toxin, a genotoxin secreted by typhoidal Salmonella serovars, has been implicated in diverse host responses ranging from DNA damage to cellular senescence. In this Research Highlight, we discuss how recent findings reveal an unexpected link between toxin‐induced DNA damage and a noncanonical interferon‐like response centered on ISG15. Using transcriptomic profiling and functional infection models, a recent report by Stark and colleagues shows that intoxicated cells mount a type‐I interferon‐like transcriptional program independent of interferons. Instead, ISG15 is upregulated via a STING‐TBK1‐dependent pathway, likely triggered by cytosolic DNA sensing following toxin‐induced damage. Strikingly, ISG15 acts independently of its canonical ISGylation activity, remaining in its free form to promote host cell survival and antibacterial defense. Importantly, they demonstrate the role of ISG15 as a key regulator of cellular fate under genotoxic stress. This divergence from canonical interferon signaling does not only add a new flavor to our understanding of the STING pathway, it also points to
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