Identification of atypical ubiquitylation and its role in inflammatory signalling. (360G-Wellcome-102894_Z_13_Z)

The overall aim of my research is elucidate key mechanisms governing inflammatory signalling and innate immune responses to invading pathogens. Pathogens are a constant threat to human health, particularly in the gastro-intestinal system. Accordingly, deregulation of inflammatory signalling leads to immunodeficiency, chronic inflammation, and cancer. Uncovering basic mechanisms controlling these processes may thus contribute to understanding the aetiology of human diseases. Pattern recognitio n receptors (PRR) recognise pathogens, and in response form multi-protein complexes where assembly and disassembly of ubiquitin chains (polyubiquitin) by ubiquitin ligases and deubiquitinases orchestrates the signals that control the subsequent inflammatory response. How polyubiquitin encodes specificity into the signals to secure an appropriate inflammatory response is not well understood. Eight types of polyubiquitin exist our cells but the cellular function of most them, termed atypical polyu biquitin, remains poorly defined. I envision that atypical polyubiquitin, like the well-studied K48- and K63-linked polyubiquitin, has important functions in innate immune regulation. In this proposal I will investigate the function and regulation of atypical polyubiquitin in PRR-dependent inflammatory signalling. I will particularly focus on signalling by bacteria-sensing receptors NOD2, TLR4, and TLR2, which have important functions in intestinal immunity. I anticipate that our results will uncover mechanisms in PRR signalling that addresses fundamental questions relating to how sensing of pathogens is translated into specific and appropriate cellular responses. Specific project aims: -Identify atypical ubiquitylation after PRR stimulation -Determine ubiquitin ligases and deubiquitinases regulating atypical polyubiquitin -Define the function of atypical polyubiquitin in pro-inflammatory signalling