Subcellular protein localization in B. subtilis

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We are working currently on several basic science and applied science projects. On the basic science side, we are investigating how proteins localize to specific subcellular regions and how cells monitor the correct assembly of large cellular structures once these proteins of interest arrive at their correct location. Such quality control mechanisms can be responsible for the incorrect morphogenesis of cells, as may occur during diseases such as cancer. In the last year, we reported several new phenomena related to "checkpoint" mechanisms that ensure cellular development proceeds properly. 1) We discovered that, during development, it is possible that certain subcellular regions of the cytoplasm can display a different physical environment (in this case, reduced pH), even though that region is contiguous with the rest of the cytoplasm. We also discovered a new cytosolic chaperone that is required in this region to activate at least one essential biosynthetic enzyme. 2) Phenotypic heterogeneity is a phenomenon in which cells that are genetically identical nonetheless display different behaviors despite being in the same environment. Such heterogeneity is sometimes used to explain why a subset of cancer cells or pathogenic bacteria are differentially resistant to therapeutics. Usually, this heterogeneity is mechanistically explained by slight differences in gene expression in different cells. We recently discovered a mechanism during development that can actively generate heterogeneity in a population via cell-cell communication. Current work is investigating how this signaling mechanism changes the metabolism of the cells that are generating the signal, and how this mechanism can lead to multicellular behaviors in a population of unicellular organisms. In another basic science study, we examined cell division in the human pathogen Staphylococcus aureus, a leading cause of hospital-acquired infections in the U.S. that is particularly problematic for immune-compromised cancer patients. The rise of antibiotic-resistant strains of S. aureus has made combatting these infections more difficult. To identify novel potential antibiotic targets that may specifically target S. aureus, we searched for new cell division genes that are specifically required for S. aureus to divide and proliferate properly, especially in the context of infection. We identified a new protein, PcdA, that ensures that S. aureus divides using the correct division plane. S. aureus that did not contain this gene a) displayed increased sensitivity to several antibiotics, and b) decreased virulence. Currently, we are investigating how perturbing cell division in S. aureus reduces its ability to cause infections. Finally, our lab is using our discoveries made in basic science to develop new technologies. Recently, we developed the "SSHEL" technology, in which we mimicked the natural assembly of bacterial spores to build synthetic spore-like "SSHEL" particles. Previously, we had shown that SSHELs may be used to deliver chemotherapeutics to specific tumors. Currently, we are investigating the utility of SSHELs in delivering other therapeutics, including peptide antigens, nucleic acids, and other small molecules.