Understanding PinT, a noncoding RNA timer of virulence gene expression

• Applicant: Professor Dr. Jörg Vogel
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 369301476

• Final Report Year: 2022

Final Report Abstract

Our discoveries highlight the dynamics of a molecular timer associated with the Salmonella infection process. We demonstrated that PinT represents a posttranscriptional level of cross-regulation between the SPI-1 and SPI-2 virulence programs. We were able to show that premature expression of SteC is prevented by PinT-mediated translational interference within the first 6 hours of infection. At later stages, repression of SteC is abrogated by an unknown mechanism, leading to synthesis of SteC, translocation, and assembly of an F-actin network around the SCV. In addition, we have created a comprehensive MAPS dataset encoding additional PinT interaction targets with a plethora of RNA molecules to be validated in follow-up studies. We would like to highlight the mRNAs of the PhoQ activator UgtL and the 30S ribosomal protein RpsV. Both PinT interactors are upregulated under SPI-2-inducing conditions and in macrophages, but also play a role in further infection stages. In particular, UgtL has an important additional function in Salmonella Typhimurium resistance to antimicrobial peptides and is required for gut colonization of streptomycin-treated mice. Therefore, it is tempting to argue that PinT, with its expanded target collection, is a new example of the growing list of mixed regulatory feedback programs consisting of sRNAs and transcription factors. And it will be a future task to study such complex networks in the regulation of important cellular processes. It will be interesting to see how the individual regulatory events involving PinT influence the timing of gene expression during the transition of Salmonella bacteria through different extracellular and intracellular stages.

Publications

• (2021) MAPS integrates regulation of actin-targeting effector SteC into the virulence control network of Salmonella small RNA PinT. Cell Reports 34(5):108722
  Correia Santos S, Bischler T, Westermann AJ, Vogel J
  
• (2022) Global RNA interactome of Salmonella discovers a 5' UTR sponge for the MicF small RNA that connects membrane permeability to transport capacity. Molecular Cell 82(3):629-44 e4
  Matera G, Altuvia Y, Gerovac M, El Mouali Y, Margalit H, Vogel J