OMPQUEST

The outer membrane of Gram-negative bacteria is a crucial barrier that mediates interactions with the colonized environment. Proteinaceous machineries in the outer membrane play crucial roles in adaptation to the colonized environment and secretion of virulence factors that promote host infection. Integral outer membrane proteins (OMPs) span the lipid bilayer by folding into ß-barrel structures. OMPs are assembled into the lipid bilayer by the ß-barrel assembly machinery (BAM). The central component of BAM, BamA, is evolutionarily conserved and its eukaryotic homolog promotes the assembly of?ß-barrel proteins in the outer mitochondrial membrane. Certain bacterial pathogens exploit these evolutionarily conserved protein transport pathways by producing virulence factors that enter mitochondrial membranes. Despite its relevance in different domains of life, the process that leads to ß-barrel protein assembly into lipid bilayers remains poorly understood. Furthermore, it is largely unknown how bacteria prevent accumulation of OMPs that are misfolded or become damaged after assembly into the outer membrane. Such outer membrane quality control is important to maintain the permeability barrier that protects bacteria against environmental chemo-physical insults. Notably, an increasing number of bacterial virulence factors, which assemble into or are secreted across the bacterial outer membrane, target mitochondria, which are central organelles of eukaryotic cell physiology. By this means, pathogenic bacteria interfere with mitochondria-regulated processes and take control of host cell fate. How such virulence factors traffic in the host cell prior to entering mitochondria remains unclear. OMPQUEST aims at dissecting these aspects of the bacterial envelope stress response and host-pathogen interaction by following complementary research approaches: i) Biogenesis of bacterial OMPs; ii) Quality control of damaged OMPs; iii) Trafficking and targeting of OMP virulence factors to mitochondria. By elucidating molecular mechanisms essential for bacterial stress survival and host infection, the proposed program will contribute to the research on novel antibiotics and new vaccination strategies capable of disarming noxious bacteria.