RT Journal Article SR Electronic T1 Spatial organization of Dectin-1 and TLR2 during synergistic crosstalk revealed by super-resolution imaging JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.04.25.489448 DO 10.1101/2022.04.25.489448 A1 Miao Li A1 Christopher Vultorius A1 Manisha Bethi A1 Yan Yu YR 2022 UL http://biorxiv.org/content/early/2022/04/25/2022.04.25.489448.abstract AB Innate immune cells recognize and elicit responses against pathogens by integrating signals from different types of cell-surface receptors. How the receptors interact in the membrane to enable their signaling crosstalk is poorly understood. Here, we reveal the nanoscale organization of TLR2 and Dectin-1, a receptor pair known to cooperate in regulating antifungal immunity, through their synergistic signaling crosstalk at macrophage cell membranes. Using super-resolution single-molecule localization microscopy, we show that discrete non-colocalized nanoclusters of Dectin-1 and TLR2 are partially overlapped during their synergistic crosstalk. Compared to when one type of receptor is activated alone, the simultaneous activation of Dectin-1 and TLR2 leads to a higher percentage of both receptors being activated by their specific ligands, and consequently an increased level of tyrosine phosphorylation. Our results depict, in nanoscale detail, how Dectin-1 and TLR2 achieve synergistic signaling through the spatial organization of their receptor nanoclusters.Competing Interest StatementThe authors have declared no competing interest.