Phosphothreonine lyases are a small family of bacterial virulence factors that are secreted into host cells during infection by some Gram-negative pathogens. Phosphothreonine lyases catalyze an irreversible phosphate β-elimination that converts phosphothreonine (pThr) to dehydrobutyrine (Dhb) on host proteins. Here, we explore the substrate profile for OspF, a phosphothreonine lyase secreted during Shigella flexneri infection, which has been previously reported to modify mitogen-activated protein kinases (MAPKs) to silence the host immune response. In this work, we use a combination of in vitro assays with synthetic phosphopeptides and bottom-up chemoproteomic profiling to uncover the OspF substrates. These studies not only show that OspF exhibits selectivity within the MAPK family but also reveal that OspF modifies a wide range of cellular targets in cellular lysates and during Shigella flexneri infection. Using a nucleophilic phosphine chemical probe, we identified and validated new OspF targets beyond the MAPK family, including Rab1A and casein kinase 2β. Together, these findings provide valuable insights about OspF substrates in Shigella flexneri infection and highlight the need for further studies to reveal its full role in the context of Shigella flexneri pathogenesis. Moreover, these data underscore the potential utility of OspF and other phospholyases as novel chemical and synthetic biology tools for site-specific protein editing.

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