2003
DOI: 10.1038/ni885
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Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A

Abstract: 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 … Show more

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Cited by 231 publications
(213 citation statements)
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“…Downstream of ROS production, cleavage of the SET complex was reported to be another critical event in GzmA-mediated death. 5,25 Given the lack of ROS generation as a trigger, it is unclear whether mGzmA would induce SET cleavage in vivo; however, we found that target cell treatment with recombinant mGzmA or GzmB with Pfp did induce cleavage of the SET complex component Ape-1 in vitro (data not shown). This correlates with reports that WT, GzmA À / À , GzmB À / À and GzmA À / À B À / À CTL were equally able to induce Ape-1 cleavage in target cells, 12 suggesting that SET complex cleavage may not always be a GzmA-specific event.…”
Section: Discussionmentioning
confidence: 86%
“…Downstream of ROS production, cleavage of the SET complex was reported to be another critical event in GzmA-mediated death. 5,25 Given the lack of ROS generation as a trigger, it is unclear whether mGzmA would induce SET cleavage in vivo; however, we found that target cell treatment with recombinant mGzmA or GzmB with Pfp did induce cleavage of the SET complex component Ape-1 in vitro (data not shown). This correlates with reports that WT, GzmA À / À , GzmB À / À and GzmA À / À B À / À CTL were equally able to induce Ape-1 cleavage in target cells, 12 suggesting that SET complex cleavage may not always be a GzmA-specific event.…”
Section: Discussionmentioning
confidence: 86%
“…All siRNA transfections were performed as previously described (Fan et al ., 2003; Fishel et al ., 2008, 2010; Logsdon et al ., 2016; Wang et al ., 2004). Briefly, 1 × 10 5 cells are plated per well of a six‐well plate and allowed to attach overnight.…”
Section: Methodsmentioning
confidence: 99%
“…From the cytosol, GzmA is transported by an unknown mechanism [that may involve its ability to bind to the mitochondrial chaperone heat shock proteins ( The su-peroxide generated by damaged mitochondria drives an ER-associated oxidative stress response complex, called the SET complex, which plays a critical role in GzmA-induced nuclear damage, into the nucleus (128,129). The SET complex contains three nucleases [the base excision repair (BER) endonuclease Ape1, an endonuclease NM23-H1, and a 5′-3′ exonuclease Trex1]; the chromatin-modifying proteins SET and pp32, which are also inhibitors of the tumor suppressor protein phosphatase 2A; and a DNA-binding protein that recognizes distorted DNA, HMGB2 (132)(133)(134)(135)(136). One of the functions of the complex is to repair abasic sites in DNA generated by oxidative damage.…”
Section: Granzyme Amentioning
confidence: 99%