Role and dynamic behavior of cyclic di-GMP signaling proteins in development and cell cycle control

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Caulobacter crescentus cell polarity and cell cycle progression are implemented by oscillating global transcriptional regulators and by spatially dynamic phospho-signaling and proteolysis pathways. Recent studies have identified the second messenger c-di-GMP as an integral part of this regulatory network. However, many of the components involved in these regulatory processes are still waiting to be identified or have not been studied in detail. Here we propose to analyze a multicomponent protein degradation platform, which assembles around the c-di-GMP effector protein PopA and is responsible for the degradation of several key proteins during G1-S phase transition. Upon binding of c-di-GMP, PopA localizes to the old cell pole, where it recruits accessory factors and substrate proteins for delivery to the polar ClpXP protease. We propose to define the entire PopA control module, including upstream diguanylate cyclases (c-di-GMP synthesis) and phosphodiesterases (c-di-GMP degradation), to characterize the mechanism used for PopA activation and subcellular localization, and to define the specific target proteins of PopA and their role in cell cycle dependent degradation. These studies will provide an in-depth view on c-di-GMP mediated protein degradation mechanisms at the molecular and cellular level and will help to generate a global and quantitative understanding of the c-di-GMP signaling network in the C. crescentus model organism.