Elucidating the Role of Novel Cell Envelope Integrity Factors of Escherichia coli

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The cell envelope surrounds and protects all bacteria, including pathogenic and beneficial species. Despite the importance of bacterial cell envelope to healthcare, much still remains unknown about the cell envelope biology. For example, in the model organism Escherichia coli, the best studied and annotated bacterium, nearly one-third of the 1,200 predicted integral membrane proteins remain poorly characterized or unannotated. Recently, systematic genetic screens were used to study functional relationships among virtually all known and putative cell envelope genes of E. coli. As a result, many novel functional connections were uncovered. I propose to focus specifically on the two novel modules of unannotated envelope genes that are functionally linked to outer membrane (OM) and lipopolysaccharide (LPS) bioprocesses. In the first module, three unannotated OM proteins (OMPs) and an uncharacterized predicted periplasmic gene displayed functional interaction with genes encoding OM biogenesis and assembly. In the second module, six unannotated inner membrane (IM) genes interacted with the components of the LPS transport (LPT) machinery. Although OM and LPS bioprocesses are well-studied, the molecular mechanisms underlying the functional connections between the uncharacterized components and the envelope integrity or assembly machineries remain unclear. Here I propose, by means of biochemical and genetic tools, to (1) determine how the unannotated OMPs and an unannotated periplasmic gene function in OM biogenesis and assembly; and (2) elucidate how unannotated IM genes function with LPT machinery factors. In addition to uncovering the functions of the aforementioned unannotated genes, on a broader scale, this research proposal will substantially deepen our understanding of cell envelope biology, and may motivate the future development of novel antibacterial therapeutics.