Molecular basis of noncanonical complement C3 activation by histamine

For fifty years the tick-over mechanism has been considered responsible for priming the activation of the complement system’s alternative pathway through the reaction of a nucleophilic water molecule with C3 yielding C3(H2O), even though the exclusivity of this role has been challenged by the existence of extrinsic proteases that can cleave circulating C3 into C3b. Here we show that the biogenic amine histamine can activate C3 by reacting with the internal thioester bond yielding a novel species that is equivalent to C3(H2O), which we have called C3h. Histamine activation of C3 occurs significantly faster than the water-mediated tick-over reaction, leading to the accelerated release of the C3a anaphylatoxin moiety, contributing to inflammation. Importantly, C3h can form an active C3 convertase enzyme that, together with the released C3a, can amplify complement activation and inflammatory responses. These results offer insight into the priming of the complement system activation and support the existence of direct crosstalk between histamine-releasing processes and complement activation.