Figure 3.

Gzm processing in cytotoxic T cells. Gzms are produced as zymogens with a leader sequence and dipeptide on the amino-terminus, which holds the Gzms in an enzymatically inactive conformation. (1) Gzms are transported and stored cytotoxic granules and their leader sequence is cleaved leaving behind a dipeptide. (2) In the cytotoxic granule cathepsins, a class of proteases present in lysosomes and cytotoxic granules, cleave the N-terminal dipeptide from the Gzms, converting them to their active conformation. (3) Gzms are stored in their active conformation in the cytotoxic granules until their release along with perforin, which mediates entry of Gzms through the target cell membrane into target cell cytosol. (4) Upon TCR activation the cytotoxic granules are released towards the immunologic synapse. Perforin mediates entry of Gzms into the cytosol of target cells where Gzms can initiate they cytotoxic activity.