Deciphering the role of phagosomal ubiquitylation in innate immunity

Phagosomes are key organelles in innate and adaptive immunity. They are membranous compartments formed by phagocytosis of large particles by specialised cells such as macrophages. Phagosomes mature by fusion with endosomal and lysosomal populations to form phagolysosomes where the foreign matter within is degraded. Several human pathogens, including Mycobacterium tuberculosis, are able to survive and replicate within phagosomes by inhibiting their maturation, highlighting the importance of understanding phagosome functions. As they are in direct contact with the prey, phagosomes are hubs for innate immune signalling, which is distinct from signalling at the plasma membrane. However, the mechanistic basis of phagosome mediated cell signalling is poorly understood. Our recent data show extensive and complex polyubiquitylation of phagosomal proteins which regulate vesicle trafficking and serve as scaffolds for the recruitment of pro-inflammatory signalling complexes. Using a combination of proteomics, cell biology and biochemistry, my team will define the role of phagosomal protein ubiquitylation in general and identify how key ubiquitin regulatory enzymes control phagosomal innate immune responses to bacterial infection. For the first time I will establish at a molecular level how ubiquitylation regulates phagosomal innate immune responses and additionally provide details about the general role of ubiquitylation in the endo-lysosomal system.