Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A.
The cytolytic T lymphocyte protease granzyme A (GzmA) initiates a caspase-independent cell death pathway. Here we report that the rate-limiting enzyme of DNA base excision repair, apurinic endonuclease-1 (Ape1), which is also known as redox factor-1 (Ref-1), binds to GzmA and is contained in the SET complex, a macromolecular complex of 270-420 kDa that is associated with the endoplasmic reticulum and is targeted by GzmA during cell-mediated death. GzmA cleaves Ape1 after Lys31 and destroys its known oxidative repair functions. In so doing, GzmA may block cellular repair and force apoptosis. In support of this, cells with silenced Ape1 expression are more sensitive, whereas cells overexpressing noncleavable Ape1 are more resistant, to GzmA-mediated death.
Fan
Zusen
Z
Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
Beresford
Paul J
PJ
Zhang
Dong
D
Xu
Zhan
Z
Novina
Carl D
CD
Yoshida
Akira
A
Pommier
Yves
Y
Lieberman
Judy
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D019757:Carbon-Oxygen Lyases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D020868:Gene Silencing; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism; D010084:Oxidation-Reduction; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D054353:Perforin; D004247:DNA; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase