The calcium-binding protein CSE links Ca²⁺ signaling with cell-cell communication in cyanobacteria

Multicellular cyanobacteria have evolved sophisticated cell-cell communication machinery to exchange, synchronize, and coordinate the efforts of individual cells. Analogous to gap junctions that have traditionally been regarded as a eukaryotic feature, multicellular cyanobacteria coordinate their cell-cell communication via septal junctions (SJs). However, the signals that regulate cell-cell communication and septal-junction assembly are largely unknown. Lately, calcium signaling has been implicated in regulating cell junctions in eukaryotes. We recently discovered a Ca²⁺-binding protein, CSE, which is exclusively found in multicellular cyanobacteria. Here, we investigate CSE as a potential link between calcium signaling and cell-cell communication. We solve the NMR structure of CSE in its Ca²⁺-bound state and revealed that CSE acts as Ca²⁺-buffer protein. Using cryo-electron tomography, we find that Δcse mutant cells display significantly fewer septal junctions as well as SJ precursors known as nanopores. This indicates that CSE is not only essential for Ca²⁺ homeostasis, but also mediates cell-cell communication via regulating SJs and nanopores formation, and establishes Ca²⁺ signaling and CSE as key players regulating cyanobacterial multicellularity. Furthermore, these findings highlight calcium signaling as a conserved principle for regulating cellular junctions in organisms that diverged a billion years ago.