Role of α2-macroglobulin in the immune responses of invertebrates

Although proteases play essential roles in the lives of all organisms, they are also important agents of disease and pathogenesis in metazoans. Most notably, proteases are essential virulence factors for a broad array of prokaryote and eukaryote parasites. One strategy used by the immune system of metazoans to defend against parasitic attack is to neutralize the toxins and essential virulence factors that allow the parasite to gain entry to the host and to survive and proliferate in the internal environment of the metazoan host. The particular defense system of interest to the present review is the system of endogenous protease inhibitors that operate to inactivate the secreted proteases utilized by invading parasites during the infection cycle within the host. Protease inhibitors are of two broad classes, active-site inhibitors that bind to and inactivate the active sites of target proteases and the alpha(2)-macroglobulin class of inhibitors that operate as opsonins to bind and mark proteases in a manner that allows the subsequent endocytosis and intracellular proteolytic degradation of the alpha(2)-macroglobulin-protease complex. Members of the alpha(2)-macroglobulin class of inhibitors interact with target proteases by the novel process of enfolding the protease into a pocket within the interior of the alpha(2)-macroglobulin molecule, which is followed by binding of the complex to the alpha(2)-macroglobulin receptor at the surfaces of macrophages and other endocytotic cells and its endocytosis and degradation. In contrast to the active-site protease inhibitors, each of which is specialized to interact with a small subset of all endopeptidases, the alpha(2)-macroglobulin inhibitors are remarkably promiscuous, binding proteases of all enzymatic classes and origins. This characteristic allows alpha(2)-macroglobulin to play an important role in immune defense because this one protein is capable of binding and neutralizing the diverse array of proteases that function as virulence factors of the diverse array of parasites out there in the environment of metazoa.