Granzyme-B Pathway
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Granzyme-B Pathway

Apoptosis of cancer cells is an active process of cell death mediated by the sequential activation of a series of caspases. In response to extrinsic or intrinsic stimuli, changes in the balance of pro- and antiapoptotic proteins may induce apoptosis. The extrinsic pathway is triggered by death receptor ligation or activation by cytotoxic granules, such as perforin and granzyme B (Ref.1). Granzyme B is the most extensively studied granzyme and is responsible for the rapid induction of caspase-dependent apoptosis (Ref.2). Also known as cytotoxic T lymphocyte associated serine esterase 1 or granzyme 2, GrB is a 32-kDa serine protease resembling chymotrypsin, and has homologues expressed in a number of different species. The gene product encoding GrB is B3500 bp long, contains five exons and four introns, and maps to chromosome 14 on the human genome. Similar to caspases, GrB has a preference for cleaving peptides immediately adjacent to aspartate (Asp) residues (Ref.3).

Granzyme-Bis unique among serine proteases because, like cysteine protease Caspases , it cleaves after aspartic acid residues and thus activates Caspase-mediated apoptosis. It cleaves and activates the apical Caspase, Caspase8, as well as Caspases3, 6, and 7 . Granzyme-Bcan directly activate Caspases3 and is capable of triggering apoptosis at multiple points of the Caspase-dependent pathway and therefore is not absolutely dependent on Caspase8 cleavage (Ref.4). Granzyme-Bcan also directly cleave BID (BH3 Interacting Death Domain). tBID (Truncated BID) disrupts the outer mitochondrial membrane to cause release of the pro-apoptotic factors CytoC (Cytochrome-C) which is crucial for activating procaspase9, HTRA2 (High Temperature Requirement Protein-A2) / OMI which blocks inhibitors of apoptosis and EndoG (Endonuclease-G) which activates DNA damage. CytC that is released from the intermembrane space binds to APAF1 (Apoptotic Protease Activating Factor-1), which recruits procaspase9 to form the apoptosome. In the apoptosome, Caspase9 is autocatalytically activated and in turn can proteolytically activate Caspases3. Cells overexpressing natural inhibitors of caspases such as BCL2 (B-Cell Leukemia-2), CRMA (Cytokine Response Modifier A) and SPI2 are sensitive to Granzyme-B mediated apoptosis. Granzyme-B also disrupts the mitochondrial transmembrane potential through an unknown mechanism and directly cleaves ICAD/DFF45 (Inhibitor of CAD/ DNA Fragmentation Factor-45) to free CAD/DFF40 (Caspase-Activated Dnase/DNA Fragmentation Factor-40) to cause DNA fragmentation. Also, the mitochondrial protein EndoG, released by the action of Granzyme-B-cleaved BID, can induce oligonucleosomal DNA damage. Therefore, Granzyme-B independently and directly activates two routes to DNA damage, even when Caspase activation is blocked (Ref.5).

In addition to targeting mitochondria and DNA degradation directly, Granzyme-B also directly cleaves several downstreamCaspase substrates. These include the sensor of DNA damage to initiate repair, PARP (Poly (ADP Ribose) Polymerase); DNA-PKcs (the Catalytic Subunit of DNA-Dependent Protein Kinase), which is involved in repairing double-stranded DNA breaks; NUMA (Nuclear Mitotic Apparatus Protein); and the nuclear-envelope intermediate-filament protein lamin-B (Ref.6). DNA-PKcsand NUMA are cut at sites distinct from those used by the Caspases, whereas lamin-B is cut at the site used by Caspase6. Increased Granzyme secretion has been implicated to play a role in the pathogenesis of rheumatoid arthritis, transplant-rejection, asthma, atopic dermatitis, psoriasis and autoimmune disorders such as Sjögren`s syndrom.