GZMB

GZMB Background

Granzyme B is a protein that in humans is encoded by the GZMB gene ^[1]. Although granzymes are structurally related to serine proteases, their substrate specificity is different. Expressed by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells ^[1], GZMB is the predominant molecular mediator of apoptosis by these cells. GZMB is a unique mammalian aspartic acid-cleaving serine protease. On T cell receptor activation, GZMB is released from the CTL cytoplasmic granules by exocytosis. It enters the target cells in the presence of the granule pore-forming protein perforin, initiating the processing of caspases and ultimate apoptosis ^[2][3]. GZMB-mediated apoptosis is also activated by adenovirus, which can effectively replace perforin. Alternatively, the apoptotic role of GZMB is also in part mediated by mitochondria. GZMB cleaves the BH3-only pro-apoptotic protein Bid. The forming truncated BID (tBID) translocates to the mitochondria together with Bax and/or Bak, which leads to the release of pro-apoptotic proteins and mitochondrial outer membrane permeabilization (MOMP), eventually triggering apoptosis ^[4]. GZMB also can directly process several known caspase substrates such as poly (ADP-ribose) polymerase (PARP), DNA-dependent protein kinase (DNA-PK), ICAD, the nuclear mitotic apparatus protein (NuMa), and lamin B. Additionally, GZMB is involved in remodeling of the matrix ^[5]. And it also has antiviral and antitumor functions ^[6]. Through the sandwich immunoassay technique, GZMB has been identified in the synovial fluid of patients with rheumatoid arthritis and the plasma of patients with bacterial and viral infections ^[7]. GZMB efficiently cleaves aggrecan, the resident proteoglycan of cartilage found in the vicinity of joint erosions, to contribute to joint damage in rheumatoid arthritis ^[8][9]. GZMB can generate autoantigens by cleaving in disordered regions and linker regions of antigens exposing new epitopes, thus causing the development of autoimmune diseases ^[10][11].

[1] Dahl CA, Bach FH, et al. Isolation of a cDNA clone encoding a novel form of granzyme B from human NK cells and mapping to chromosome 14 [J]. Hum Genet. 1990, 84 (5): 465-70.
[2] Catalfamo, M. and Henkart, P. A. Perforin and the granule exocytosis cytotoxicity pathway [J]. Curr. Opin. Immunol. 2003, 15, 522-527.
[3] Keefe, D., Shi, L., et al. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis [J]. Immunity. 2005, 23, 249-262.
[4] Waterhouse, N. J., Sedelies, K. A., et al. Role of Bid-induced mitochondrial outer membrane permeabilization in granzyme B-induced apoptosis [J]. Immunol. Cell Biol. 2006, 84, 72-78.
[5] Buzza, M. S., Zamurs, L., et al. Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin [J]. J. Biol. Chem. 2005, 280, 23549-23558.
[6] Trapani, J. A. and Sutton, V. R. Granzyme B: pro-apoptotic, antiviral and antitumor functions [J]. Curr. Opin. Immunol. 2003, 15, 533-543.
[7] Tak PP, Spaeny‐Dekking L, et al. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA) [J]. Clin Exp Immunol 1999; 116: 366- 70.
[8] Froelich CJ, Zhang X, et al. Human granzyme B degrades aggrecan proteoglycan in matrix synthesized by chondrocytes [J]. J Immunol 1993; 151: 7161- 71.
[9] Ronday HK, van der Laan WH, et al. Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis [J]. Rheumatology (Oxford) 2001; 40: 55- 61.
[10] Boivin WA, Cooper DM, et al. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma [J]. Laboratory Investigation; A Journal of Technical Methods and Pathology. 2009, 89 (11): 1195-220.
[11] Darrah E, Rosen A . Granzyme B cleavage of autoantigens in autoimmunity [J]. Cell Death and Differentiation. 2010, 17 (4): 624-32.