Exploring the Strategies of Bacterial Subversion of the Host Ubiquitin System: The Mechanism of Novel E3 Ligases (NEL) from Shigella

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The aim of this project is to elucidate the mechanism by which bacterial ubiquitin ligases undermine the innate immune response of an infected cell. Our understanding will help to uncover new therapeutic strategies to fight the emerging threat of antimicrobial resistance. The innate immune response is the first line of defence against bacterial infections. It involves activation of a variety of cellular reactions, which cause inflammation of the infected tissue. The activation steps of the inflammatory response depend to a great extent on the ubiquitylation machinery of the cell. The ubiquitylation machinery consists of a cascade of different enzymes, which act in sequence to modify target proteins with ubiquitin chains. Ubiquitin chains consist of the small protein ubiquitin. The attachment of ubiquitin chains is tightly regulated and catalysed by a class of enzymes known as E3 ubiquitin ligases. Many pathogenic bacteria deploy a set of E3 ubiquitin ligases which they introduce into the cytosol of the infected host cell. These bacterial ubiquitin ligases, known as NELs (Novel E3 Ligase), are capable to modify components of the host ubiquitylation machinery with ubiquitin. The activity of the bacterial NELs interferes with normal function of the host ubiquitylation machinery which ultimately subverts the innate immune response in favour of the invading pathogen. It is currently unknown how NELs highjack the host ubiquitylation machinery to modify their target proteins. The human pathogen Shigella flexneri are highly infectious bacteria which are responsible for a severe form of dysentery known as shigellosis. Shigellosis a significant cause of morbidity and mortality worldwide. Some NELs from Shigella are targeting the linear ubiquitin chain assembly complex LUBAC which results in functional interference of the complex. LUBAC is a key component of the ubiquitylation machinery and required for the activation of the inflammatory response upon bacterial infection. We will use a combination of structural and biophysical techniques to determine the molecular mechanism by which the NEL IpaH1.4 from Shigella modifies LUBAC with ubiquitin and uncover how this modification inhibits LUBAC activity. Our findings will shed light on the molecular mechanism of Shigella pathogenesis and may provide new routes to restrict bacterial infections.