Understanding the functional diversity of NOD-like receptors (NLRs) in Streptomyces

Jordan, Max (2024) Understanding the functional diversity of NOD-like receptors (NLRs) in Streptomyces. Doctoral thesis, University of East Anglia.

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Abstract

NOD-like receptors (NLRs) represent a well-characterised family of eukaryote immune receptors. NLRs are defined by a tripartite domain architecture consisting of a C-terminal series of superstructure-forming repeats which recognise an activating signal, a central STAND ATPase domain acting as a molecular switch and an N-terminal effector domain which mediates downstream signalling. NLRs are particularly well-characterised in plant immunity where they recognise pathogen-derived effector proteins to trigger the immune response. Despite this, their role in bacteria is largely unknown, including in the Streptomyces genus of multicellular actinomycetes crucial for antibiotic production.

In this thesis, I characterise the NLRome encoded within model Streptomyces strains, revealing striking diversity at the domain level and a key role for NLRs in regulating bacterial specialised metabolism. Included within these NLRomes are amyloid-forming NLRs, enriched in multicellular bacteria. Based on the role of homologous NLRs in eukaryote immunity, I attempt to characterise the role of these NLRs in vivo in antiphage immunity for the first time. I then focus on the role of the NLR AfsR in Streptomyces specialised metabolism. I characterise the molecular mechanism of AfsR with reference to that of plant NLRs. I confirm that they both utilise ATP-binding for activation, can be activated by conserved ‘autoactive’ mutations and suggest a conserved role for oligomerisation in the two systems. The generation of autoactive AfsR represents a powerful tool for further characterisation in vivo, which I use to map the AfsR regulon using ChIP-seq and increase production of doxorubicin, a key anticancer drug, in Streptomyces peucetius.

Overall, I demonstrate the key, albeit underappreciated, role of NLRs in bacteria, highlight how understanding NLRs can enable both fundamental and commercially relevant advances and suggest that the NLR domain architecture represents an important strategy across the tree of life for tight control of a downstream pathway.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Kitty Laine
Date Deposited:	03 Jun 2025 11:55
Last Modified:	03 Jun 2025 11:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99385
DOI:

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