Granzyme A

Definition:

Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse. It cleaves after Lys or Arg. Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-B (GSDMB), releasing the pore-forming moiety of GSDMB, thereby triggering pyroptosis and target cell death. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Cleaves the nucleosome assembly protein SET after 'Lys-189', which disrupts its nucleosome assembly activity and allows the SET complex to translocate into the nucleus to nick and degrade the DNA.

References:

[1]. Clara Hink-Schauer, et al. Crystal structure of the apoptosis-inducing human granzyme A dimer. Nat Struct Biol. 2003 Jul;10(7):535-40. [Content Brief]

[2]. Zusen Fan, et al. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol. 2003 Feb;4(2):145-53. [Content Brief]

[3]. A Hameed, et al. Characterization of three serine esterases isolated from human IL-2 activated killer cells. J Immunol. 1988 Nov 1;141(9):3142-7. [Content Brief]

[4]. Zhiwei Zhou, et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020 May 29;368(6494):eaaz7548. [Content Brief]

[5]. O Krähenbühl, et al. Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes. J Immunol. 1988 Nov 15;141(10):3471-7. [Content Brief]

[6]. P J Beresford, et al. Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. J Biol Chem. 2001 Nov 16;276(46):43285-93. [Content Brief]

[7]. Dipanjan Chowdhury, et al. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell. 2006 Jul 7;23(1):133-42. [Content Brief]

[8]. Zusen Fan, et al. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell. 2003 Mar 7;112(5):659-72. [Content Brief]

[9]. H K Gershenfeld, et al. Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1184-8. [Content Brief]

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