A protease-initiated model of wound detection

Wounds trigger surrounding cells to initiate repair, but it is unclear how cells detect wounds. The first known wound response of epithelial cells is a dramatic increase in cytosolic calcium, which occurs within seconds, but it is not known what initiates this calcium response. Specifically, is there an instructive signal detected by cells surrounding wounds? Here we identify a signal transduction pathway in epithelial cells initiated by the G-protein coupled receptor Methuselah-like 10 (Mthl10) activated around wounds by its cytokine ligands, Growth-blocking peptides (Gbps). Gbps are present in unwounded tissue in latent form, requiring proteolytic activation for signaling. Multiple protease families can activate Gbps, suggesting it acts as a detector to signal the presence of several proteases. We present experimental and computational evidence that proteases released during cell lysis serve as the instructive signal from wounds, liberating Gbp ligands to diffuse to the Mthl10 receptors on epithelial cells and activate downstream release of calcium. Thus, the presence of a nearby wound is signaled by the activation of a Gbp protease detector, sensitive to multiple proteases released after cellular damage.