{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nGranzyme K is a serine protease abundantly expressed by cytotoxic lymphocytes that can trigger rapid, caspase‐independent cell death. Mechanistic studies have shown that GzmK induces the generation of reactive oxygen species and collapses the mitochondrial inner membrane potential by cleaving Bid into its active fragment tBid, thereby promoting mitochondrial outer membrane permeabilization and the release of apoptotic factors (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]). In influenza virus–infected mice, single‐cell analyses revealed that high levels of granzyme K transcripts in tetramer‐positive CD8⁺ T cells correlate with cytotoxic function, yet knockout studies indicate that absence of granzyme K does not impair overall viral clearance (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its cytotoxic role, extracellular granzyme K functions as a proinflammatory mediator. In virus‐infected models, GzmK released by cytotoxic T cells stimulates primary macrophages to process and secrete interleukin‐1β independently of ATP receptor signaling, thereby contributing to the orchestration of the inflammatory response (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]). In a bacterial sepsis model, mice deficient in granzyme K displayed lower clinical inflammatory scores—even though improved survival was achieved only by targeting granzyme A—underscoring distinct inflammatory roles of these proteases (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]). Moreover, the preferential presence of granzyme K in inflamed tissues supports its role as an inflammatory mediator (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHigh‐resolution N-terminomics analyses have further defined granzyme K’s substrate repertoire, revealing subtle differences in specificity compared to related granzymes and thereby providing insight into its unique enzymatic functions (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]). Complementary gene coexpression studies in various brain structures have integrated granzyme K into a network with other genes, such as Map3k1 and Il6st, which has even been associated with predisposition to catalepsy, hinting at potential roles beyond classical cytotoxic or inflammatory functions (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tongbiao Zhao, Honglian Zhang, Yuming Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M611006200"}], "href": "https://doi.org/10.1074/jbc.M611006200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17308307"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17308307"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Misty R Jenkins, Joseph A Trapani, Peter C Doherty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB-/- mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Viral Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/vim.2008.0036"}], "href": "https://doi.org/10.1089/vim.2008.0036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18788942"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18788942"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lars T Joeckel, Cody C Allison, Marc Pellegrini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Granzyme K-deficient mice show no evidence of impaired antiviral immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/icb.2017.35"}], "href": "https://doi.org/10.1038/icb.2017.35"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28428612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28428612"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "L T Joeckel, R Wallich, P Martin, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/bjd/ljac017"}], "href": "https://doi.org/10.1093/bjd/ljac017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36652225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36652225"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kim Plasman, Hans Demol, Philip I Bird, et al. 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