Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity

Abstract

Granzyme K (Gzm K) and granzyme A (GzmA) are the only two tryptases among all the granzymes. Tryptase activity is necessary for cytotoxic T lymphocyte (CTL)/nature killer (NK) cells-mediated cytolysis. Granzyme K might be a potent granzyme to rescue the activity of granzyme A. Granzyme K expresses at high levels in CD56(high) NK cells, memory CD8+ T cells and CD56+ T cells. We recently demonstrated human granzyme K induces rapid cell death with rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. Moreover, Granzyme K can induce rapid reactive oxygen species (ROS) generation and collapse of mitochondrial inner membrane potential. Blockade of reactive oxygen species accumulation suppresses granzyme K-induced cell death. However, it is unknown about how reactive oxygen species generate in Granzyme K-mediated apoptosis. Here we found the redox factor-1/apurinic apyrimidinic endonuclease Ape1 can antagonize reactive oxygen species generation. Overexpression of Ape1 inhibits, whereas silencing Ape1 expression potentiates reactive oxygen species accumulation under treatment with oxidative reagents or loading with granzyme K. Ape1 is a physiological substrate of granzyme K. Ape1 cleavage by granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death.