Apoptosis and survival - Granzyme A signaling

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 [1].

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 [2], [3], [4]. This results in NK or CD8+ T cells polarization and maturation of cytotoxic granule inclusive Granzyme A and Perforin. Synaptotagmin VII [5], [6], Rab-27A and Unc-13 homolog D (Munc13-4) are essential regulators of cytotoxic granule maturation and fusion with the plasma membrane [7], [8], [9]. 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 [10]. Perforin and Granzyme A release from cytotoxic granules into the immunological synapse formed between target and immune (CD8+ T or NK) cells [1].

Granzyme A delivery to the cytosol, mitochondria and nucleus is dependent on Perforin [3], [11], [12].

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 [1], [12].

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) [13], DNA-bending protein High-mobility group box 2 (HMG2) [14] and the Base excision repair endonuclease APEX nuclease 1 (APEX) [15].

Granzyme A is translocated into nucleus and cleaves Lamin A/C and Lamin B1 [16], Histone cluster 1 H1b (Histone H1b), SET [13], HMG2 [14] and the tails of core histones Histone H2 and Histone H3 [17]. This disruption opens up chromatin to DNases [18]. Cleavage of SET liberates the Granzyme A-activated DNase NDPK A and results in DNA damage by single-stranded nicks [13], [19]. It is shown that NDPK A also activates tumor protein p53 that can induce p53-dependent apoptosis [20]. Granzyme A cleaves X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku70) [21], 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 [22]. DNA and mitochondria damages, lamina disruption, and loss of mitochondrial transmembrane potential cause DNA degradation, nucleus fragmentation, and lead to apoptosis in target cells [4], [18], [23].

References:

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