Apoptosis and survival - Granzyme B signaling

Granzyme B signaling

Granzyme B is abundant serine protease, which is responsible for rapid induction of caspase-dependent apoptosis, promoting caspase activation directly and indirectly, through proteolysis of the Bcl-2 family proteins [1], [2].

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 [3], [4], [5]. This results in NK or CD8+ T cells polarization and maturation of cytotoxic granule inclusive Granzyme B and Perforin. Synaptotagmin VII [6], [7], Rab-27A and Unc-13 homolog D (Munc13-4) are essential regulators of cytotoxic granule maturation and fusion with the plasma membrane [8], [9], [10]. These granules are localized in contact with the target cells and contain also lysosome-resident proteins Lysosomal-associated membrane protein 1 and 2 (LAMP1 and LAMP2) and CD63 [11]. Perforin and Granzyme B release from cytotoxic granules into the immunological synapse formed between effector cells [12].

Perforin allows Granzyme B access to cytosolic and nuclear substrates [13], [14], [15]. In the cytoplasm human Granzyme B cleaves BH3 interacting domain death agonist (Bid) more efficiently than it cleaves caspases [1]. Proteolysis of Bid by Granzyme B results in the translocation of the C terminus of Bid (tBid) to mitochondria. In mitochondria outer membrane Granzyme B also cleaves anti-apoptotic Bcl-2 family protein Myeloid cell leukemia sequence 1 (Mcl-1) [16], [17]. Those interactions induce the release of mitochondrial Cytochrome c somatic (Cytochrome C) and Diablo homolog (Smac/Diablo) into the cytosol [2]. Cytochrome C is involved in the apoptosome pathway together with Apoptotic peptidase activating factor 1 (Apaf-1) and activated Caspase 9 [18], [19]. Release of mitochondrial Smac/Diablo represses the inhibitors of apoptosis in target cell, making caspases more readily activated directly by Granzyme B [19].

On the other hand, Granzyme B directly processes Caspase-8, and Caspase-10, and then activates Caspase-3, and Caspase-7. Caspase-3 is the central effector caspase within the Granzyme B-initiated caspase cascade. It completes maturation of Caspase-8 and Caspase-10 and activates Caspase-2, Caspase-6 and Caspase-9 [1].

Granzyme B directly cleaves caspase substrates, like nuclear Lamin B1 [20], Nuclear mitotic apparatus protein 1 (NUMA1) [2], [21], Poly (ADP-ribose) polymerase 1 (PARP-1) [22], [23], and cytoplasmic DNA fragmentation factor 45kDa alpha polypeptide (ICAD) [24], and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) [25]. Caspases also cleave Lamin A/C [15].

Cleavage of structural components of nucleoskeleton, Lamins and NUMA1, results in nuclear integrity disruption [20], [26]. Degradation of ICAD induces release of DNA fragmentation factor 40kDa beta polypeptide (DFF40 (CAD)) that degrades chromosomal DNA [24], [27]. Cleavage of PARP-1 promotes apoptosis by preventing DNA repair-induced survival [28]. Degradation of ROCK2 results in membrane blebbing [2], [25]. Granzyme B cleaves Tubulin alpha and induces microtubule polymerization and cytoskeletal collapse [29]. Proteolysis of Fibroblast growth factor receptor 1 (FGFR1) and transmembrane Notch homolog 1 translocation-associated (NOTCH1 (NEXT)) results in target cell isolation from survival signals from extracellular environment and enhances programmed cell death, apoptosis [22].

References:

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