7th joint conference "Joint Microbiology & Infection Conference 2024" of the DGHM and VAAM

Abstract: Because of their photosynthesis-dependent lifestyle, cyanobacteria evolved sophisticated regulatory mechanisms to adapt to oscillating day-night metabolic changes. How they coordinate the metabolic switch between autotrophic and glycogen-catabolic metabolism in light and darkness is poorly understood. Recently, we showed that the second messenger c-di-AMP is implicated in diurnal regulation1. To unravel the signaling functions of c-di-AMP, we identified the cyanobacterial c-di-AMP receptor proteins. The carbon-sensor protein SbtB was identified as a major c-di-AMP receptor1. We found that c-di-AMP–bound SbtB interacts with the glycogen-branching enzyme GlgB. Accordingly, both c-di-AMP-free (ΔdacA) and ΔsbtB–deficient mutants displayed impaired glycogen synthesis and nighttime survival1. To gain better understanding of cellular processes regulated by SbtB or c-di-AMP, we compared the metabolomic, transcriptomics, and proteomic landscapes of both mutants2,3. While our results indicate that the cellular roles of SbtB is restricted to carbon/glycogen metabolism1-5, the ΔdacA lethality seems a result of dysregulation of multiple metabolic processes2,3. These processes include photosynthesis and redox regulation, which lead to elevated levels of intracellular ROS and glutathione2. Further, we showed an impact of c-di-AMP on transcription/transitional regulations, ion homeostasis, and especially on central carbon metabolism. Adding to its cellular functions catalog, for first time, we show physiologically that c-di-AMP signaling influences on nitrogen metabolism, implying new cellular roles for c-di-AMP in controlling nitrogen homeostasis2. Additionally, we found that the cyanobacterial pilus biogenesis and natural competence are regulated by c-di-AMP and show that the ComFB signaling protein is a novel c-di-AMP-receptor protein6, widespread in bacterial phyla, and required for DNA uptake. 
 
1.	Selim KA, Haffner M, Burkhardt M, Mantovani O, Neumann N, Albrecht R, Seifert R, Krüger L, Stülke J, Hartmann MD, Hagemann M, Forchhammer K. Diurnal metabolic control in cyanobacteria requires perception of second messenger signaling molecule c-di-AMP by the carbon control protein SbtB. Sci Adv. 2021; 7(50):eabk0568.
2.	Haffner M, Mantovani O, Spät P, Maček B, Hagemann M, Forchhammer K, Selim KA. Diurnal rhythm causes metabolic crises in the cyanobacterial mutants of c-di-AMP signalling cascade. BioRxiv 2023; doi: https://doi.org/10.1101/2023.11.14.567006.
3.	Mantovani O, Reimann V, Haffner M, Herrmann FP, Selim KA, Forchhammer K, Hess WR, Hagemann M. The impact of the cyanobacterial carbon-regulator protein SbtB and of the second messengers cAMP and c-di-AMP on CO2 -dependent gene expression. New Phytol. 2022; 234(5):1801-1816.
4.	Selim KA, Haffner M, Mantovani O, Albrecht R, Zhu H, Hagemann M, Forchhammer K, Hartmann MD. Carbon signaling protein SbtB possesses atypical redox-regulated apyrase activity to facilitate regulation of bicarbonate transporter SbtA. PNAS. 2023; 120(8):e2205882120.
5.	Selim KA, Haase F, Hartmann MD, Hagemann M, Forchhammer K. PII-like signaling protein SbtB links cAMP sensing with cyanobacterial inorganic carbon response. PNAS. 2018; 115(21):E4861-E4869.
6.	Samir S, Doello S, Zimmer E, Haffner M, Enkerlin AM, Müller T, Dengler L, Lambidis SP, Sivabalasarma S, Albers S-V, Selim KA. The second messenger c-di-AMP controls natural competence via ComFB signaling protein. BioRxiv 2023; doi: https://doi.org/10.1101/2023.11.27.568819 

c-di-AMP signaling in cyanobacteria: a new paradigm in controlling cellular homeostasis

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