Mechanism controlling TG2 export. Schematic showing different events occurring upon P2X7R activation by ATP. (A) Ion channel activity triggers intracellular signaling that results in actin reorganization and microvesicle shedding. However, these microvesicles do not contain TG2. (B) Coupling between P2X7R and pannexin-1 triggers hemichannel pore opening. TG2 secretion is unaffected by blocking pannexin-1 channels. (C) P2X7R itself can form a membrane pore through conformational changes and, possibly, receptor oligomerization in a process that involves the extended intracellular C-terminal sequence. TG2 secretion is associated with this membrane pore activity but independent of ion channel function, and occurs in conjunction with thioredoxin-1 (Trx) externalization. As thioredoxin can reactivate TG2 functionally blocked in an oxidized state, this might ensure that externalized TG2 has transamidation activity. Flot2, flotillin-2.
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