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Granzyme A Induces a Cell Death Pathway Independently of Caspases Activation
Jia-Wen Miao, Fang-Qiu Li*
Clinical School of Medical College of Nanjing University; Center of Medical Laboratory Sciences of the People‘s Liberation Army, Nanjing General Hospital of Nanjing Command, Nanjing 210002, China
Abstract: Granzyme A， the most abundant serine protease in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells， is released into the immunological synapse formed between the killer cell and its target， delivered to the cytosol of target cells via perforin， concentrate in target cell nuclei， and induces caspases-independent cell death. A special target of the granzyme A cell death pathway is an endoplasmic reticulum-associated complex， called the SET complex， which contains three granzyme A substrates， the nucleosome assembly protein SET， the DNA-binding protein HMG-2， and the base excision repair endonuclease Ape1. The SET complex also contains the tumor suppressor protein pp32 and the granzyme A-activated DNase NM23-H1， which is inhibited by SET. Granzyme A cleavage of SET releases the NM23-H1. Cleavage of Ape1 by granzyme A interferes with the ability of the target cell to repair itself. This is a novel cell death pathway initiated by granzyme A.
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