BACTOCOMPASS

In living organisms, the ability of cells to move across surfaces (cell motility) is a universal feature of multicellularity. In eukaryots, cell motility is essential a different stages of embryogenesis and to maintain an organism’s general homeostasis, for tissue repair or to protect against pathogenic invasions. In bacteria, cell motility is linked to pathogenesis and biofilm formation, which enhances the resistance of the community to environmental insults. Because of their extraordinary resistance to antibiotics and chemicals in general, biofilms pose problems both for public health and the industry. Given their general biological importance, the mechanisms underlying motility regulation have been studied intensively. Remarkably, it appears that the core regulation mechanisms involving small G-proteins of the Ras superfamily is conserved despite the evolutionary distance that separates eukaryots and prokaryots. In eukaryotic systems, these regulations usually involve an arsenal of small G-proteins and their regulators, making it difficult to elucidate the regulatory mechanism. Remarkably the deltaproteobacterium Myxococcus xanthus, uses a single G-protein, MglA, to regulate its direction of movement in response to environmental signals. In this process, MglA associates with GTP and binds to the leading cell pole where it activates the motility machinery. The spatial regulation of MglA depends on a second protein, MglB, a member of the emerging class of Roadblock/Longins of small G-protein regulators, that localizes at the opposite cell pole. At this pole, MglB acts as an MglA GTPase Activating Protein (GAP) and activates the hydrolysis of the MglA-bound GTP, preventing the accumulation of MglA at that pole. Remarkably, this polarity axis formed by MglA and MglB is invertible such that when the localization of MglA and MglB is switched synchronously to the opposite cell poles, the cells stop and resumes movement in the opposite direction (reversal). Reversals are under genetic control and provoked by the signaling activity of the Frz pathway, a bacterial chemosensory-like system, linking environmental changes to motility regulation. The sophisticated experimental tractability of Myxococcus and the relatively low number of regulators makes it a powerful model system to study the regulation of motility at high resolution. However, there are still fundamental questions that need to be solved before an integrated model may be constructed. Starting from preliminary observations, this consortium of three groups with complementary expertise will address three main questions : (i) How does MglB regulate the GTPase activity of MglA and is the mechanism conserved in other Rb-Lg-G-protein pairs? (ii) How does Frz signaling activate the synchronous spatial switching of MglAB? (iii) How is motility regulation by MglAB integrated at the multicellular scale to culminate into cooperative behaviors? Combining reductionist approaches from the realms of structural biology and single cell studies to global approaches such as modeling and genomics, this project aims to define new research directions to understand how autonomous single cell behaviors can be integrated into the cooperation of thousands of individuals, a general question in developmental and evolution biology.