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granzyme B leakage-induced cell death
IFGP family protein 2
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Granzyme B (approved gene symbol GZMB) is one of the serine proteases (see: granzymes) that is located in the granules of cytotoxic T-cells and NK-cells (for an inhibitor see: PI9 [proteinase inhibitor-9]). This protein is known also as Granzyme 2 or serine protease B (CSP-B for cytotoxic serine protease B) (Klein et al, 1989) or CCP1 [cytotoxic cell protease-1] or Asp-ase (Trapani et al, 1993). Granzyme B has been identified also as CGL1 [cathepsin G-like-1] by Hanson et al (1990) as a serine protease expressed only in cytotoxic T-lymphocytes after cell activation. The rat homolog has been identified as RNKP1 [rat natural killer protease-1] (Fell et al, 2002). Granzyme B has been described as CTLA-1 [cytotoxic T-lymphocyte-associated serine esterase-1] by Brunet et al (1986) who identified this and two other mRNA transcripts in various cytotoxic T-cells that were not found or at considerably lower levels in non-cytotoxic lymphoid cells. Rat Granzyme B has been described as fragmentin-2. Thia and Trapani (2007) have reported that the granzyme B gene is highly polymorphic in wild mice but essentially invariant in common inbred laboratory strains. Smyth et al (1995) have shown that the proform of human granzyme B is activated through cleavage by dipeptidyl peptidase 1.
Rissoan et al (2002) have reported that granzyme B is expressed in resting and activated plasmacytoid dendritic cells. Much lower levels are found in monocytes, resting T-cells, B-cells, activated granulocytes, and activated monocyte-derived dendritic cells.
Granzyme B is crucial for the rapid induction of target cell cell death by apoptosis induced by interaction cytotoxic T-cells. The receptor has been identified by Motyka et al (2000) as mannose-6-phosphate receptor, which is identical with the receptor for IGF-2. This receptor functions as a death receptor for granzyme B during cytotoxic T-cell induced apoptosis as inhibition of Granzyme B with this receptor prevents binding and uptake of Granzyme B as well as the induction of apoptosis.
Granzyme B has been shown to proteolytically activate several caspases involved in cell death by apoptosis, including caspase-3 and caspase-7 (Quan et al, 1996; Chinnaiyan et al, 1996; Van de Craen et al, 1998). Activation of the proform of caspase-7 involves prior processing of capase-3 by granzyme B. Caspase-3 then removes the propeptide of caspase-7, allowing activation by granzyme B (Yang et al, 1998). Processing of other caspases by granzyme B may also be indirect (Van de Craen et al, 1998).
Barry et al (2000) have demonstrated that granzyme B directly cleaves the pro-apoptotic molecule BID, bypassing the need for caspase-8 activation of BID. Ida et al (2003) have reported that granzyme B is involved in rapid activation-induced natural killer cell death. This type of cell death, termed granzyme B leakage-induced cell death, involves leakage of granzyme B from intracellular granules into the cytoplasm. Evidence for granzyme B leakage includes the formation of complexes between granzyme B and its inhibitor, serine proteinase inhibitor PI9, as well as colocalization of granzyme B and PI9. A major determinant of cell death is an excess of leaked granzyme B over its inhibitor. Leaked Granzyme B cleaves the pro-apoptotic protein BID, allowing it to be directed to mitochondrial membranes.
Adrain et al (2006) have reported that granzyme B targets the cytoskeleton by cleaving and removing the acidic C-terminal tail of alpha-tubulin. This markedly enhances rates of microtubule polymerization in vitro. Delivery of Granzyme B into target cells promotes dramatic reorganization of the microtubule network in a manner independent of caspase activity.
Loeb et al (2006) have reported that Notch-1 and FGFR1 are substrates of granzyme B, suggesting that granzyme B activates pro-death functions within a target, but also plays a role by inactivating pro-growth signals to cause cell death.
Knickelbein et al (2008) have described a nonlethal mechanism of viral inactivation in which granzyme B degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.
Froelich et al (1993) have shown that granzyme B degrades the aggrecan proteoglycan in matrix synthesized by chondrocytes.
For an immunotoxin based on the use of granzyme B see also: immunoGrB.
For other entries pertaining to cell death mechanisms see also the Apoptosis and Cell Death Dictionary section of this encyclopedia.
Copyright © 2012 by H IBELGAUFTS. All rights reserved.
ENTRY LAST MODIFIED: March 2009
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