Table 2.

Substrates and functions of all mouse Gzms and human homologues if known ¹.

	Known Substrates	Function
Gzm A *	Gasdermin B [47], SET [48,49], pro–IL-1β [50], NDUFS3 [51], histone H1 [52], HMGB2 [52], and ApeI [53]	Gzm A’s primary role is to activate and release pro-inflammatory cytokines from target cells. Mouse and human Gzm A induces pyroptosis in human cells through the cleavage and activation of human gasdermin B (there is no known mouse homologue for gasdermin B) [47]. Additionally, Gzm A can target multiple nuclear and mitochondrial targets that likely contribute to its specific form of caspase-independent cytotoxicity.
Gzm B *	Mouse and Human: pro-caspase 3, pro-caspase 7 Human only: Bid, inhibitor of caspase-activated DNase (ICAD), pro-caspase 8 [46]	Gzm B cell death results in the activation of the caspase cascade and induction of canonical apoptosis in both mouse and humans.
Gzm C	Orphan (undetermined)	Gzm C induces a caspase-independent form of cell death that results in single-stranded DNA nicking and mitochondrial swelling. Gzm C does not activate BID or the CAD nuclease, suggesting it has alternative targets and initiates different pathways from Gzm B [54].
Gzm D	Orphan (undetermined)	Undetermined
Gzm E	Orphan (undetermined)	Undetermined
Gzm F	Orphan (undetermined)	Gzm F has been suggested to induce a “necroptotic-like” form of cell death[55]. Gzm F-induced cell death is caspase-independent, induces mitochondrial damage independent of the Bid pathway, results in rupture of the cellular membrane, single stranded DNA nicking, cellular organelle damage, and extensive vacuolization of the cytoplasm [55]. This death phenotype strongly resembles necroptosis [56,57].
Gzm G	Orphan (undetermined)	Undetermined
Gzm K *	SET [58,59], β-tubulin [60], APE1 [59,61,62]	Gzm K induces single-stranded DNA damage, mitochondrial dysfunction, and generation of reactive oxygen species (ROS), and cell membrane damage through a caspase-independent mechanism [58,59].
Gzm M *	Human: nucleophosmin [63], FADD [64], survivin [65], ICAD [66] Mouse and Human: alpha-Tubulin [67]	Gzm M induces apoptosis in humans though its function is undetermined in mice. Gzm M does not induce cell death in multiple mouse tumor models in vitro but mouse Gzm M can induce apoptosis in target human cancer cells in vitro [67].
Gzm N	Orphan (undetermined)	To our knowledge, Gzm N has not been found to be significantly expressed in T cells or other immune cells. Its expression has been found in the testes in one study, specifically in spermatocytes and spermatids, though its biological function was not determined [68].

¹ Gzms without a known substrate are designated orphan and mouse Gzms with a known human homologue with the same name are marked with an asterisk.