Granzyme A signaling
Granzyme A is abundant serine protease, which induces
apoptosis by caspase-independent pathways. Granzyme A is
released by Cytotoxic T lymphocytes (CD8+ T cells) and Natural Killer (NK) cells as
response on cell infection, cancer transformation, and antigens presentation .
CD8+ T cells cytotoxicity is activated after cell infection, cancer transformation,
and allogenic antigens presentation by MHC class I. NK cells are activated after
recognition of allogenic or modified antigens on MHC class I-negative target cell surface
, , . This results in NK or CD8+ T cells
polarization and maturation of cytotoxic granule inclusive Granzyme
A and Perforin. Synaptotagmin
VII , ,
Rab-27A and Unc-13 homolog D
(Munc13-4) are essential regulators of cytotoxic granule
maturation and fusion with the plasma membrane , , . These granules are localized in contact with the target cells and contain also
lysosome-resident proteins Lysosomal-associated membrane protein 1
(LAMP1), Lysosomal-associated membrane protein 2
(LAMP2) and CD63 . Perforin and Granzyme
A release from cytotoxic granules into the immunological synapse formed
between target and immune (CD8+ T or NK) cells .
Granzyme A delivery to the cytosol, mitochondria and
nucleus is dependent on Perforin , , .
Granzyme A accesses the mitochondrial matrix and cleaves
the complex I protein NADH dehydrogenase Fe-S protein 3
(NDUFS3), subunit of the NADH: ubiquinone oxidoreductase
complex I, to interfere with inhibition of oxidative phosphorylation cycle.
NDUFS3 cleavage requires mitochondrial transmembral
potential. Granzyme A directly causes a rapid increase in
superoxide anion O(,2)('-).
O(,2)('-) is key to nuclear translocation of another
Granzyme A substrate, SET
complex , .
Endoplasmic reticulum-associated SET complex contains
Non-metastatic cells 1 protein expressed in
(NDPK A), Three prime repair exonuclease
1 (TREX1), Acidic nuclear
phosphoprotein 32 family member A (PHAP1
(pp32)) and three Granzyme A substrates,
nucleosome assembly protein SET nuclear oncogene
(SET) , DNA-bending protein
High-mobility group box 2 (HMG2)  and the
Base excision repair endonuclease APEX nuclease 1 (APEX)
Granzyme A is translocated into nucleus and cleaves
Lamin A/C and Lamin B1 , Histone cluster 1 H1b (Histone
H1b), SET ,
HMG2  and the tails of core histones
Histone H2 and Histone H3
. This disruption opens up chromatin to DNases . Cleavage
of SET liberates the Granzyme
A-activated DNase NDPK A and results in
DNA damage by single-stranded nicks , . It is shown that NDPK A also activates tumor
protein p53 that can induce
p53-dependent apoptosis .
Granzyme A cleaves X-ray repair complementing defective
repair in Chinese hamster cells 6 (Ku70) , a
key component of the PK-DNA ligase 4 complex that recruits DNA ligase
IV and X-ray repair complementing defective repair in Chinese hamster
cells 4 (XRCC4) for double-strand break repair . DNA and mitochondria damages, lamina disruption,
and loss of mitochondrial transmembrane potential cause DNA
degradation, nucleus fragmentation, and lead to apoptosis in target cells , , .
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