BacNLR - Functional diversity of NLRs in multicellular bacteria

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BacNLR is an ambitious high-risk/high-gain program to reveal the functional diversity of nucleotide-binding oligomerisation domain like receptors (NLRs) in multicellular bacteria that goes beyond their well-established role in eukaryotic immunity. NLRs are found in all domains of life, yet little is known about their role in bacteria because their existence has only recently been fully recognised.Unlike most bacteria, species of antibiotic-producing multicellular Streptomyces encode multiple NLRs with distinct signalling domains, suggesting that these proteins have diverse functions. We found that in Streptomyces several NLR-like proteins are linked to antibiotic production, development or share homology to eukaryotic NLRs shown to induce programmed cell death. We thereforehypothesise that NLR-signalling plays a crucial and so far unexplored role in several important cellular processes, including antibiotic production, immunity and multicellular behaviour.To reveal these novel cellular roles, I developed a method to synthetically activate NLR signalling in Streptomyces, overcoming the need to identify a specific stimulus for NLR activation. This breakthrough enables us now to study the impact of NLRs on regulating antibiotic production and to discover new and possibly unexpected cellular roles. In BacNLR, we will use bioinformatics to identify the full spectrum of NLR diversity in bacteria; determine the diverse functions of NLRs in multicellular Streptomyces and define the molecular mechanisms that underpin these functions.BacNLR will not only uncover new roles of NLR signalling but also reveal undamental new principles in the regulation of antibiotic production, providing an innovative strategy to combat the rise in drug-resistant pathogens. The gained knowledge will expand our current models about the evolution, and functional diversity of NLRs across all kingdoms and serve as a framework for engineeringNLR signalling pathways in bacteria.