Living cells consist of one or more membrane-bound compartments. Cell membranes are composed of lipids and proteins that are involved in transport of solutes, energy conversion, signaling and secretion. Efficient membrane protein biogenesis and turnover are two opposite facets of an essential cellular task that ensures correct functioning of membrane-bound compartments. One central objective of our research is to decipher the pathways of regulation, biogenesis and turnover of integral membrane proteins. Furthermore we are interested in understanding how misfolded or damaged membrane proteins are detected and removed to preserve membrane integrity and functionality. To this end, we have developed two research axes.
Project 1: In Gram negative bacteria, the outermost lipid bilayer (or outer membrane) represents the first line of interaction with the colonized environment. The outer membrane of bacterial pathogens promotes both defense and attack strategies to interact with the host. It forms an essential permeability barrier that protects the bacterial cell from external chemo-physical insults and it secretes virulence factors that are ultimately targeted to the host. Integral outer membrane proteins (OMPs) span the lipid bilayer by folding into Beta-barrel structures. OMPs are susceptible to damage by oxidizing agents produced by the host innate immune response and external proteases. Elucidating how bacteria cope with these stresses is paramount to understand the molecular processes of host-pathogen interaction. We use Escherichia coli and Neisseria meningitidis as model organisms to study how damaged OMPs are detected and degraded thus preserving the functionality of the outer membrane as a permeability barrier and as a platform for protein secretions.
Project 2: Mitochondria are essential organelles of eukaryotic cells that evolved from an endosymbiotic relationship between a Gram negative bacterium and a eukaryotic cell ancestor. Mitochondria play different roles in many physiological processes, such as energy conversion, calcium homeostasis, lipid metabolism, iron-sulfur cluster biogenesis, and apoptosis. Reflecting their evolutional origin, mitochondria are surrounded by two membranes and harbor evolutionarily conserved protein transport machineries. The outer membrane contains integral membrane proteins that fold into beta barrel structures, similarly to bacterial OMPs. Certain bacterial pathogens exploit evolutionarily conserved protein transport pathways to target virulence factors to mitochondria and interfere with mitochondria-regulated processes. We are interested in understanding how OMPs and other virulence factors are released from bacteria and how they traffic in the host cell and target mitochondria.
By elucidating the molecular mechanisms that are essential for stress survival and host infection, our work will contribute to the research on novel antibiotics and new vaccination strategies capable of disarming noxious bacteria.