GZMB (Homo sapiens)

Description [+]

Synonyms: GZMB, GRB, GRANZYME B
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: Granzyme B Precursor (EC 3.4.21.79)(Granzyme-2)(T-cell serine protease 1-3E)(Cytotoxic T-lymphocyte proteinase 2)(Lymphocyte protease)(SECT)(Cathepsin G-like 1)(CTSGL1)(CTLA-1)(Fragmentin-2)(Human lymphocyte protein)(HLP)(C11) [Source:UniProtKB/Swiss-Prot;Acc:P10144]
Family: other
Process:
Pathways:
Criteria: manually curated
Curator comment: Human Granzyme B induces apoptosis mainly through Bid cleavage.
Mouse ortholog(s): Gzme Gzmc Gzmn Gzmb Gzmf Gzmg Gzmd
WIKI: GZMB-H_sapiens

References [+]

Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway.
Pinkoski MJ, Waterhouse NJ, Heibein JA, Wolf BB, Kuwana T, Goldstein JC, Newmeyer DD, Bleackley RC, Green DR
Cytotoxic T lymphocytes kill virus-infected and tumor cell targets through the concerted action of proteins contained in cytolytic granules, primarily granzyme B and perforin. Granzyme B, a serine proteinase with substrate specificity similar to the caspase family of apoptotic cysteine proteinases, is capable of cleaving and activating a number of death proteins in target cells. Despite the ability to engage the death pathway at multiple entry points, the preferred mechanism for rapid induction of apoptosis by granzyme B has yet to be clearly established. Here we use time lapse confocal microscopy to demonstrate that mitochondrial cytochrome c release is the primary mode of granzyme B-induced apoptosis and that Bcl-2 is a potent inhibitor of this pivotal event. Caspase activation is not required for cytochrome c release, an activity that correlates with cleavage and activation of Bid, which we have found to be cleaved more readily by granzyme B than either caspase-3 or caspase-8. Bcl-2 blocks the rapid destruction of targets by granzyme B by blocking mitochondrial involvement in the process. J Biol Chem. 2001 Apr 13;276(15):12060-7. Epub 2001 Jan 12.

Human and murine granzyme B exhibit divergent substrate preferences.
Cullen SP, Adrain C, Luthi AU, Duriez PJ, Martin SJ
The cytotoxic lymphocyte protease granzyme B (GzmB) can promote apoptosis through direct processing and activation of members of the caspase family. GzmB can also cleave the BH3-only protein, BID, to promote caspase-independent mitochondrial permeabilization. Although human and mouse forms of GzmB exhibit extensive homology, these proteases diverge at residues predicted to influence substrate binding. We show that human and mouse GzmB exhibit radical differences in their ability to cleave BID, as well as several other key substrates, such as ICAD and caspase-8. Moreover, pharmacological inhibition of caspases clonogenically rescued human and mouse target cells from apoptosis initiated by mouse GzmB, but failed to do so in response to human GzmB. These data demonstrate that human and murine GzmB are distinct enzymes with different substrate preferences. Our observations also illustrate how subtle differences in enzyme structure can radically affect substrate selection. J Cell Biol. 2007 Feb 12;176(4):435-44. Epub 2007 Feb 5.

References from Mouse ortholog(s):

Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation.
Darmon AJ, Ley TJ, Nicholson DW, Bleackley RC
Cytotoxic T lymphocytes (CTLs) are able to recognize and destroy target cells bearing foreign antigen using one of two distinct mechanisms: granule- or Fas-mediated cytotoxicity. The exact mechanisms involved in the induction of apoptotic cell death remain elusive; however, it seems likely that a family of cysteine proteases related to interleukin-1beta converting enzyme are involved. One family member, CPP32, has been identified as an intracellular substrate for granzyme B, a CTL-specific serine protease responsible for the early induction of target cell DNA fragmentation. Here we use cytolytic cells from granzyme B-deficient mice to confirm that cleavage and activation of CPP32 represents a nonredundant role for granzyme B and that this activation plays a role in the induction of DNA fragmentation in target cells, a signature event for apoptotic cell death. A peptide inhibitor of CPP32-like proteases confirmed the function of these enzymes in fragmentation. 51Cr release was not suppressed under these conditions, suggesting that granzyme B cleavage of CPP32 is primarily involved in the induction of DNA fragmentation and not membrane damage during CTL-induced apoptosis. J Biol Chem. 1996 Sep 6;271(36):21709-12.

Granzyme B activates procaspase-3 which signals a mitochondrial amplification loop for maximal apoptosis.
Metkar SS, Wang B, Ebbs ML, Kim JH, Lee YJ, Raja SM, Froelich CJ
Granzyme B (GrB), acting similar to an apical caspase, efficiently activates a proteolytic cascade after intracellular delivery by perforin. Studies here were designed to learn whether the physiologic effector, GrB-serglycin, initiates apoptosis primarily through caspase-3 or through BH3-only proteins with subsequent mitochondrial permeabilization and apoptosis. Using four separate cell lines that were either genetically lacking the zymogen or rendered deficient in active caspase-3, we measured apoptotic indices within whole cells (active caspase-3, mitochondrial depolarization [DeltaPsim] and TUNEL). Adhering to these conditions, the following were observed in targets after GrB delivery: (a) procaspase-3-deficient cells fail to display a reduced DeltaPsim and DNA fragmentation; (b) Bax/Bak is required for optimal DeltaPsim reduction, caspase-3 activation, and DNA fragmentation, whereas BID cleavage is undetected by immunoblot; (c) Bcl-2 inhibits GrB-mediated apoptosis (reduced DeltaPsim and TUNEL reactivity) by blocking oligomerization of caspase-3; and (d) in procaspase-3-deficient cells a mitochondrial-independent pathway was identified which involved procaspase-7 activation, PARP cleavage, and nuclear condensation. The data therefore support the existence of a fully implemented apoptotic pathway initiated by GrB, propagated by caspase-3, and perpetuated by a mitochondrial amplification loop but also emphasize the presence of an ancillary caspase-dependent, mitochondria-independent pathway. J Cell Biol. 2003 Mar 17;160(6):875-85. Epub 2003 Mar 10.

Structure & Sequence [+]

Source	Domain Name	Start	End
PFAM A	Trypsin	21	240

Evolution [+]

Name	Relationship	Species
GZMB	orthology	Chimpanzee
IPI00687114.2	orthology	Cow
T_rubripes_ENSTRUP00000003184	orthology	Fugu
G_aculeatus_ENSGACP00000009787	orthology	Gasterosteus
GZMB	orthology	Gorilla
XP_001914771.1	orthology	Horse
XP_001487931.2	orthology	Horse
XP_001488563.1	orthology	Horse
XP_001488456.2	orthology	Horse
XP_001488243.2	orthology	Horse
XP_001488476.2	orthology	Horse
E_caballus_ENSECAP00000013774	orthology	Horse
XP_001488328.2	orthology	Horse
Q2A6L4_HORSE	orthology	Horse
XP_001488365.2	orthology	Horse
Q70T74_HORSE	orthology	Horse
GZMB	orthology	Macaca
O_latipes_ENSORLP00000025366	orthology	Medaka
O_latipes_ENSORLP00000025360	orthology	Medaka
Gzme	orthology	Mouse
Gzmd	orthology	Mouse
Gzmc	orthology	Mouse
Gzmn	orthology	Mouse
Gzmb	orthology	Mouse
Gzmf	orthology	Mouse
Gzmg	orthology	Mouse
GZMB	orthology	Orangutan
NP_703196.1	orthology	Rat
RGD1561819	orthology	Rat
NP_001103116.1	orthology	Rat
GRZ1_RAT	orthology	Rat
Q63224_RAT	orthology	Rat
NKP1_RAT	orthology	Rat
NP_599159.1	orthology	Rat
X_tropicalis_ENSXETP00000053312	orthology	Xenopus
si:dkey-21e2.7	orthology	Zebrafish
si:dkey-21e2.10	orthology	Zebrafish
D_rerio_ENSDARP00000096104	orthology	Zebrafish
si:dkey-21e2.13	orthology	Zebrafish
A8WIQ3_DANRE	orthology	Zebrafish
si:dkey-21e2.8	orthology	Zebrafish
NP_001108166.1	orthology	Zebrafish
si:dkey-21e2.15	orthology	Zebrafish
si:dkey-78l4.11	orthology	Zebrafish
si:dkey-77m18.1	orthology	Zebrafish
si:dkey-78l4.5	orthology	Zebrafish
si:dkey-21e2.13	orthology	Zebrafish
NP_989788.1	paralogy	Chicken
IPI00598771.2	paralogy	Chicken
CMA1	paralogy	Chimpanzee
GZMH	paralogy	Chimpanzee
CTSG	paralogy	Chimpanzee
GZMA	paralogy	Chimpanzee
IPI00712239.3	paralogy	Cow
IPI00709745.3	paralogy	Cow
KLK14	paralogy	Cow
DDN1_BOVIN	paralogy	Cow
IPI00906593.1	paralogy	Cow
IPI00907670.1	paralogy	Cow
IPI00904277.1	paralogy	Cow
IPI00904894.1	paralogy	Cow
IPI00722008.2	paralogy	Cow
IPI00718201.3	paralogy	Cow
IPI00717480.2	paralogy	Cow
GRAA_BOVIN	paralogy	Cow
IPI00906030.1	paralogy	Cow
GZMB	paralogy	Dog
GZMH	paralogy	Dog
CMA1_CANFA	paralogy	Dog
C_familiaris_ENSCAFP00000035309	paralogy	Dog
KLK14	paralogy	Dog
Q91515_FUGRU	paralogy	Fugu
T_rubripes_ENSTRUP00000043133	paralogy	Fugu
ELANE	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000004304	paralogy	Gasterosteus
GZMA	paralogy	Gorilla
GZMH	paralogy	Gorilla
CMA1	paralogy	Gorilla
CTSG	paralogy	Gorilla
E_caballus_ENSECAP00000018861	paralogy	Horse
XP_001488926.2	paralogy	Horse
E_caballus_ENSECAP00000000569	paralogy	Horse
KLK14	paralogy	Horse
GZMA	paralogy	Horse
GZMH	paralogy	Human
CTSG	paralogy	Human
GZMA	paralogy	Human
KLK14	paralogy	Human
CMA1	paralogy	Human
A_carolinensis_ENSACAP00000007818	paralogy	Lyzard
GZMA	paralogy	Lyzard
A_carolinensis_ENSACAP00000017221	paralogy	Lyzard
A_carolinensis_ENSACAP00000017229	paralogy	Lyzard
GZMH	paralogy	Macaca
GZMA	paralogy	Macaca
CTSG	paralogy	Macaca
CMA1	paralogy	Macaca
GZMA	paralogy	Medaka
ELANE	paralogy	Medaka
O_latipes_ENSORLP00000017065	paralogy	Medaka
O_latipes_ENSORLP00000017036	paralogy	Medaka
CTSG	paralogy	Monodelphis
KLK14	paralogy	Monodelphis
CMA1	paralogy	Monodelphis
PRSSL1	paralogy	Monodelphis
GZMA	paralogy	Monodelphis
Mcpt8	paralogy	Mouse
Mcptl	paralogy	Mouse
Gzma	paralogy	Mouse
Ctsg	paralogy	Mouse
Cma2	paralogy	Mouse
Mcpt2	paralogy	Mouse
Mcpt3	paralogy	Mouse
Mcpt1	paralogy	Mouse
Cma1	paralogy	Mouse
CTSG	paralogy	Orangutan
GZMA	paralogy	Orangutan
GZMH	paralogy	Orangutan
CMA1	paralogy	Orangutan
O_anatinus_ENSOANP00000017204	paralogy	Ornithorhynchus
CFD	paralogy	Ornithorhynchus
O_anatinus_ENSOANP00000014158	paralogy	Ornithorhynchus
Q9GME0_ORNAN	paralogy	Ornithorhynchus
O_anatinus_ENSOANP00000002245	paralogy	Ornithorhynchus
O_cuniculus_ENSOCUP00000011323	paralogy	Rabbit
CMA1	paralogy	Rabbit
GZMH	paralogy	Rabbit
O_cuniculus_ENSOCUP00000001767	paralogy	Rabbit
MCPT1_RAT	paralogy	Rat
NP_703198.1	paralogy	Rat
Q6IE57_RAT	paralogy	Rat
Q9Z1D3_RAT	paralogy	Rat
MCPT2_RAT	paralogy	Rat
Klk14	paralogy	Rat
MCPT8_RAT	paralogy	Rat
TRY1_RAT	paralogy	Rat
MCPT4_RAT	paralogy	Rat
GRZ2_RAT	paralogy	Rat
NP_062196.1	paralogy	Rat
Q6IE09_RAT	paralogy	Rat
Q6IE11_RAT	paralogy	Rat
Cma1	paralogy	Rat
NP_058841.1	paralogy	Rat
Q6IE56_RAT	paralogy	Rat
X_tropicalis_ENSXETP00000000761	paralogy	Xenopus
BC088038.1	paralogy	Xenopus
BC088027.1	paralogy	Xenopus
CTSG	paralogy	Zebra finch
GZMA	paralogy	Zebra finch

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0006508	proteolysis	biological_proccess	IEA
GO:0019835	cytolysis	biological_proccess	IEA
GO:0006915	apoptosis	biological_proccess	TAS
GO:0006922	cleavage of lamin	biological_proccess	IDA
GO:0004252	serine-type endopeptidase activity	mollecular_function	IEA
GO:0003824	catalytic activity	mollecular_function	IEA
GO:0008233	peptidase activity	mollecular_function	IEA
GO:0004252	serine-type endopeptidase activity	mollecular_function	TAS
GO:0005515	protein binding	mollecular_function	IPI
GO:0005829	cytosol	cell_component	EXP
GO:0001772	immunological synapse	cell_component	TAS
GO:0005634	nucleus	cell_component	TAS
GO:0005737	cytoplasm	cell_component	IDA

Check GO Evidence Codes here

Information from other databases [+]