title: 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.
authors.affiliation: National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Tongbiao
authors.initials: T
authors.lastname: Zhao
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts; D045304:Cytochromes c / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D053804:Granzymes / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D053804:Granzymes; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes