Granzyme-A Pathway
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Granzyme-A Pathway

The granzymes (granule enzymes) are a family of highly homologous serine proteases contained in cytotoxic granules of innate and adaptive immune killer cells. Their major job is to induce cell death to eliminate viruses and tumor cells. There are five human granzymes and ten mouse granzymes, expressed from three gene clusters. Granzyme A and granzyme B (GzmA, GzmB) are the most abundant granzymes. A pore-forming protein, Perforin, and serine proteases,Granzyme, are key effector molecules of CL. These toxins are stored within secretory granules, which exocytose their contents in response to immune synapse formation between the CL and virus-infected or transformed target cell (Ref.1 and 2). Granzyme- Acauses characteristic features of apoptosis, including membrane blebbing, loss of mitochondrial transmembrane potential, nuclear fragmentation and chromatin condensation; however, instead of the usual apoptotic double-stranded oligonucleosomal DNA fragmentation, Granzyme- Acauses a distinctive form of DNA damage that is single-stranded DNA nicking (Ref.3).

During the induction of cell death, Granzyme-Atargets a newly identified 270–420 kDa ER (Endoplasmic Reticulum)-associated complex, known as the SET complex, which contains two tumour-suppressor proteins, pp32 and GAAD (Granzyme-A-Activated DNase)/NM23H1 and three Granzyme-A substrates the nucleosome-assembly protein SET; the DNA-binding protein HMG2 (High-Mobility Group Protein-2) and the rate-limiting base-excision repair enzyme APE1 (Apurinic/Apyrimidinic Endonuclease-1). Indeed, the proteins in this complex translocate rapidly to the nucleus in response to an increase in the level of ROS (Reactive Oxygen Species) and after Granzyme-A loading with perforin. Granzyme-A destroys three members of the SET complex, including the nucleosome-assembly protein SET, the base-excision repair enzyme APE1 and HMG2, a DNA-binding protein that might be involved in recognizing damaged DNA. When these proteins are destroyed, the DNA-nicking protein NM23-H1 is free to cut DNA and the breaks are not repaired. NM23-H1 is the GAAD and SET is its inhibitor, IGAAD (Inhibitor of GAAD) (Ref.4).

During Granzyme- A loading with perforin, the linker histone H1 is completely degraded and the tails are cut from the core histones. This opens up chromatin and enhances DNA fragmentation. Granzyme- A also destroys the nuclear lamins, the key intermediate-filament component of the nuclear envelope, which anchor chromatin and the nuclear-pore complexes (NPCs) to provide nuclear integrity. After Granzyme- A loading with perforin, caspases are not cleaved or activated, and downstream caspase substrates are by and large untouched. Cytochrome C is not released from mitochondria, although the mitochondrial membrane is depolarized and mitochondria become dysfunctional, as shown by the increased level of ROS. Moreover, Granzyme A-induced cell death is not inhibited by the overexpression of BCL2 (Ref.5).