{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T14:25:40Z","timestamp":1794407140003,"version":"4.9.0"},"reference-count":178,"publisher":"Walter de Gruyter GmbH","issue":"7-9","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Granzymes are a family of trypsin-like serine proteinases (TLSP) produced by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. They play critical roles in immune defense by inducing diverse forms of programmed cell death (e.g., apoptosis, pyroptosis, and necroptosis) in infected or abnormal cells. Here, we review current information on the structural mechanisms underlying the activation, substrate specificity, and inhibition of the five human granzymes (GzmA, GzmB, GzmH, GzmK, and GzmM). We highlight how specific variations of the canonical trypsin fold allow these five proteinases to display entirely distinct substrate specificities. We emphasize the role of allosteric mechanisms, such as exosites and dimerization, in expanding their substrate recognition profiles far beyond simple P1 cleavage site requirements. We discuss the rapidly growing evidence on the contribution of dysregulated granzyme activity to various inflammatory and autoimmune diseases. Finally, we explore emerging therapeutic strategies targeting granzymes, aiming to either enhance their beneficial cytotoxic effects (e.g., in cancer immunotherapy and infection) or inhibit their pathological roles in chronic inflammation and autoimmunity. Despite significant progress, open questions remain regarding the full spectrum of physiological granzyme substrates, their precise synergistic actions\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    , and the translational challenges of applying\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    findings to complex clinical contexts.\n                  <\/jats:p>","DOI":"10.1515\/hsz-2025-0251","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:55:53Z","timestamp":1783947353000},"page":"315-340","source":"Crossref","is-referenced-by-count":1,"title":["On the structure and function of granzymes, the deadly squad of cytotoxic lymphocytes"],"prefix":"10.1515","volume":"407","author":[{"given":"Jos\u00e9 Luis","family":"Gardeaz\u00e1bal-Torbado","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology , University of Barcelona (UB) , E-08028 , Barcelona , Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB) , E-08028 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2687-5801","authenticated-orcid":false,"given":"Eva","family":"Est\u00e9banez-Perpi\u00f1\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology , University of Barcelona (UB) , E-08028 , Barcelona , Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB) , E-08028 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Fuentes-Prior","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology , University of Barcelona (UB) , E-08028 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"2026111114033354246_j_hsz-2025-0251_ref_001","doi-asserted-by":"crossref","unstructured":"Adrain, C., Duriez, P.J., Brumatti, G., Delivani, P., and Martin, S.J. (2006). The cytotoxic lymphocyte protease, granzyme B, targets the cytoskeleton and perturbs microtubule polymerization dynamics. J.\u00a0Biol. Chem. 281: 8118\u20138125, https:\/\/doi.org\/10.1074\/jbc.m509361200.","DOI":"10.1074\/jbc.M509361200"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_002","doi-asserted-by":"crossref","unstructured":"Afonina, I.S., Tynan, G.A., Logue, S.E., Cullen, S.P., Bots, M., L\u00fcthi, A.U., Reeves, E.P., McElvaney, N.G., Medema, J.P., Lavelle, E.C., et al.. (2011). Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1\u03b1. Mol. Cell 44: 265\u2013278, https:\/\/doi.org\/10.1016\/j.molcel.2011.07.037.","DOI":"10.1016\/j.molcel.2011.07.037"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_003","doi-asserted-by":"crossref","unstructured":"Alimonti, J.B., Shi, L., Baijal, P.K., and Greenberg, A.H. (2001). Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition. J.\u00a0Biol. Chem. 276: 6974\u20136982.","DOI":"10.1074\/jbc.M008444200"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_004","doi-asserted-by":"crossref","unstructured":"Ambrose, A.R., Hazime, K.S., Worboys, J.D., Niembro-Vivanco, O., and Davis, D.M. (2020). Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles. Proc. Natl. Acad. Sci. U.S.A. 117: 23717\u201323720, https:\/\/doi.org\/10.1073\/pnas.2010274117.","DOI":"10.1073\/pnas.2010274117"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_005","doi-asserted-by":"crossref","unstructured":"Andrade, F., Roy, S., Nicholson, D., Thornberry, N., Rosen, A., and Casciola-Rosen, L. (1998). Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 8: 451\u2013460, https:\/\/doi.org\/10.1016\/s1074-7613(00)80550-6.","DOI":"10.1016\/S1074-7613(00)80550-6"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_006","doi-asserted-by":"crossref","unstructured":"Andrade, F., Fellows, E., Jenne, D.E., Rosen, A., and Young, C. (2007). Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J. 26: 2148\u20132157, https:\/\/doi.org\/10.1038\/sj.emboj.7601650.","DOI":"10.1038\/sj.emboj.7601650"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_007","doi-asserted-by":"crossref","unstructured":"Atkinson, E.A., Barry, M., Darmon, A.J., Shostak, I., Turner, P.C., Moyer, R.W., and Bleackley, R.C. (1998). Cytotoxic T lymphocyte-assisted suicide. J.\u00a0Biol. Chem. 273: 21261\u201321266, https:\/\/doi.org\/10.1074\/jbc.273.33.21261.","DOI":"10.1074\/jbc.273.33.21261"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_008","doi-asserted-by":"crossref","unstructured":"Aubert, A., Jung, K., Hiroyasu, S., Pardo, J., and Granville, D.J. (2024). Granzyme serine proteases in inflammation and rheumatic diseases. Nat. Rev. Rheumatol. 20: 361\u2013376, https:\/\/doi.org\/10.1038\/s41584-024-01109-5.","DOI":"10.1038\/s41584-024-01109-5"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_009","doi-asserted-by":"crossref","unstructured":"Aubert, A., Liu, A., Kao, M., Goeres, J., Richardson, K.C., Nierves, L., Jung, K., Nabai, L., Zhao, H., Orend, G., et al.. (2024). Granzyme B cleaves tenascin-C to release its C-terminal domain in rheumatoid arthritis. JCI Insight 9: e181935, https:\/\/doi.org\/10.1172\/jci.insight.181935.","DOI":"10.1172\/jci.insight.181935"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_010","doi-asserted-by":"crossref","unstructured":"Aybay, E., Ryu, J., Fu, Z., Akula, S., Enriquez, E.M., Hallgren, J., Wernersson, S., Olsson, A.K., and Hellman, L. (2023). Extended cleavage specificities of human granzymes A and K, two closely related enzymes with conserved but still poorly defined functions in T and NK cell-mediated immunity. Front. Immunol. 14: 1211295, https:\/\/doi.org\/10.3389\/fimmu.2023.1211295.","DOI":"10.3389\/fimmu.2023.1211295"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_011","doi-asserted-by":"crossref","unstructured":"Bade, B., Boettcher, H.E., Lohrmann, J., Hink-Schauer, C., Bratke, K., Jenne, D.E., Virchow, J.C., and Luttmann, W. (2005). Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes. Int. Immunol. 17: 1419\u20131428, https:\/\/doi.org\/10.1093\/intimm\/dxh320.","DOI":"10.1093\/intimm\/dxh320"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_012","doi-asserted-by":"crossref","unstructured":"Bai, Y., Pan, Y., and Liu, X. (2025). Mechanistic insights into gasdermin-mediated pyroptosis. Nat. Rev. Mol. Cell Biol. 26: 501\u2013521, https:\/\/doi.org\/10.1038\/s41580-025-00837-0.","DOI":"10.1038\/s41580-025-00837-0"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_013","doi-asserted-by":"crossref","unstructured":"B\u00e1lint, \u0160., M\u00fcller, S., Fischer, R., Kessler, B.M., Harkiolaki, M., Valitutti, S., and Dustin, M.L. (2020). Supramolecular attack particles are autonomous killing entities released from cytotoxic T\u00a0cells. Science 368: 897\u2013901, https:\/\/doi.org\/10.1126\/science.aay9207.","DOI":"10.1126\/science.aay9207"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_014","doi-asserted-by":"crossref","unstructured":"Barry, M. and Bleackley, R.C. (2002). Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol. 2: 401\u2013409, https:\/\/doi.org\/10.1038\/nri819.","DOI":"10.1038\/nri819"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_015","doi-asserted-by":"crossref","unstructured":"Barry, M., Heibein, J.A., Pinkoski, M.J., Lee, S.F., Moyer, R.W., Green, D.R., and Bleackley, R.C. (2000). Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving bid. Mol. Cell. Biol. 20: 3781\u20133794, https:\/\/doi.org\/10.1128\/mcb.20.11.3781-3794.2000.","DOI":"10.1128\/MCB.20.11.3781-3794.2000"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_016","doi-asserted-by":"crossref","unstructured":"Bell, J.K., Goetz, D.H., Mahrus, S., Harris, J.L., Fletterick, R.J., and Craik, C.S. (2003). The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity. Nat. Struct. Mol. Biol. 10: 527\u2013534, https:\/\/doi.org\/10.1038\/nsb944.","DOI":"10.1038\/nsb944"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_017","doi-asserted-by":"crossref","unstructured":"Bertheloot, D., Latz, E., and Franklin, B.S. (2021). Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell. Mol. Immunol. 18: 1106\u20131121, https:\/\/doi.org\/10.1038\/s41423-020-00630-3.","DOI":"10.1038\/s41423-020-00630-3"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_018","doi-asserted-by":"crossref","unstructured":"Bird, C.H., Sutton, V.R., Sun, J., Hirst, C.E., Novak, A., Kumar, S., Trapani, J.A., and Bird, P.I. (1998). Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell. Biol. 18: 6387\u20136398, https:\/\/doi.org\/10.1128\/mcb.18.11.6387.","DOI":"10.1128\/MCB.18.11.6387"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_019","doi-asserted-by":"crossref","unstructured":"Bird, C.H., Sun, J., Ung, K., Karambalis, D., Whisstock, J.C., Trapani, J.A., and Bird, P.I. (2005). Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol. Cell. Biol. 25: 7854\u20137867, https:\/\/doi.org\/10.1128\/mcb.25.17.7854-7867.2005.","DOI":"10.1128\/MCB.25.17.7854-7867.2005"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_020","doi-asserted-by":"crossref","unstructured":"Bode, W., Fehlhammer, H., and Huber, R. (1976). Crystal structure of bovine trypsinogen at 1.8 \u00c5 resolution. I. Data collection, application of Patterson search techniques and preliminary structural interpretation. J.\u00a0Mol. Biol. 106: 325\u2013335, https:\/\/doi.org\/10.1016\/0022-2836(76)90089-9.","DOI":"10.1016\/0022-2836(76)90089-9"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_021","doi-asserted-by":"crossref","unstructured":"Bode, W., Schwager, P., and Huber, R. (1978). The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. The refined crystal structures of the bovine trypsinogen-pancreatic trypsin inhibitor complex and of its ternary complex with Ile-Val at 1.9 \u00c5 resolution. J.\u00a0Mol. Biol. 118: 99\u2013112, https:\/\/doi.org\/10.1016\/0022-2836(78)90246-2.","DOI":"10.1016\/0022-2836(78)90246-2"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_022","doi-asserted-by":"crossref","unstructured":"Bode, W., Walter, J., Huber, R., Wenzel, H.R., and Tschesche, H. (1984). The refined 2.2-\u00c5 (0.22-nm) X-ray crystal structure of the ternary complex formed by bovine trypsinogen, valine-valine and the Arg15 analogue of bovine pancreatic trypsin inhibitor. Eur. J.\u00a0Biochem. 144: 185\u2013190, https:\/\/doi.org\/10.1111\/j.1432-1033.1984.tb08447.x.","DOI":"10.1111\/j.1432-1033.1984.tb08447.x"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_023","doi-asserted-by":"crossref","unstructured":"Boivin, W.A., Cooper, D.M., Hiebert, P.R., and Granville, D.J. (2009). Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab. Invest. 89: 1195\u20131220, https:\/\/doi.org\/10.1038\/labinvest.2009.91.","DOI":"10.1038\/labinvest.2009.91"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_024","doi-asserted-by":"crossref","unstructured":"Boivin, W.A., Shackleford, M., Vanden Hoek, A., Zhao, H., Hackett, T.L., Knight, D.A., and Granville, D.J. (2012). Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-\u03b21. PLoS One 7: e33163, https:\/\/doi.org\/10.1371\/journal.pone.0033163.","DOI":"10.1371\/journal.pone.0033163"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_025","doi-asserted-by":"crossref","unstructured":"Bouwman, A.C., van Daalen, K.R., Crnko, S., ten Broeke, T., and Bovenschen, N. (2021). Intracellular and extracellular roles of granzyme K. Front. Immunol. 12: 677707, https:\/\/doi.org\/10.3389\/fimmu.2021.677707.","DOI":"10.3389\/fimmu.2021.677707"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_026","doi-asserted-by":"crossref","unstructured":"Bovenschen, N., de Koning, P.J.A., Quadir, R., Broekhuizen, R., Damen, J.M.A., Froelich, C.J., Slijper, M., and Kummer, J.A. (2008). NK cell protease granzyme M targets \u03b1-Tubulin and disorganizes the microtubule network. J.\u00a0Immunol. 180: 8184\u20138191, https:\/\/doi.org\/10.4049\/jimmunol.180.12.8184.","DOI":"10.4049\/jimmunol.180.12.8184"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_027","doi-asserted-by":"crossref","unstructured":"Bovenschen, N., Quadir, R., van den Berg, A.L., Brenkman, A.B., Vandenberghe, I., Devreese, B., Joore, J., and Kummer, J.A. (2009). Granzyme K displays highly restricted substrate specificity that only partially overlaps with granzyme A. J.\u00a0Biol. Chem. 284: 3504\u20133512, https:\/\/doi.org\/10.1074\/jbc.m806716200.","DOI":"10.1074\/jbc.M806716200"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_028","doi-asserted-by":"crossref","unstructured":"Bromley, S.K., Burack, W.R., Johnson, K.G., Somersalo, K., Sims, T.N., Sumen, C., Davis, M.M., Shaw, A.S., Allen, P.M., and Dustin, M.L. (2001). The immunological synapse. Annu. Rev. Immunol. 19: 375\u2013396, https:\/\/doi.org\/10.1146\/annurev.immunol.19.1.375.","DOI":"10.1146\/annurev.immunol.19.1.375"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_029","doi-asserted-by":"crossref","unstructured":"Broz, P. (2025). Pyroptosis: molecular mechanisms and roles in disease. Cell Res. 35: 334\u2013344, https:\/\/doi.org\/10.1038\/s41422-025-01107-6.","DOI":"10.1038\/s41422-025-01107-6"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_030","doi-asserted-by":"crossref","unstructured":"Buzza, M.S., Zamurs, L., Sun, J., Bird, C.H., Smith, A.I., Trapani, J.A., Froelich, C.J., Nice, E.C., and Bird, P.I. (2005). Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. J.\u00a0Biol. Chem. 280: 23549\u201323558, https:\/\/doi.org\/10.1074\/jbc.m412001200.","DOI":"10.1074\/jbc.M412001200"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_031","doi-asserted-by":"crossref","unstructured":"Buzza, M.S., Dyson, J.M., Choi, H., Gardiner, E.E., Andrews, R.K., Kaiserman, D., Mitchell, C.A., Berndt, M.C., Dong, J.F., and Bird, P.I. (2008). Antihemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor. J.\u00a0Biol. Chem. 283: 22498\u201322504, https:\/\/doi.org\/10.1074\/jbc.m709080200.","DOI":"10.1074\/jbc.M709080200"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_032","doi-asserted-by":"crossref","unstructured":"Caruso, J.A. and Reiners, J.J. (2006). Proteolysis of HIP during apoptosis occurs within a region similar to the BID loop. 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Commun. 13: 1029, https:\/\/doi.org\/10.1038\/s41467-022-28596-y.","DOI":"10.1038\/s41467-022-28596-y"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_035","doi-asserted-by":"crossref","unstructured":"Chao, Z., Mei, Q., Yang, C., Luo, J., Liu, P., Peng, H., Guo, X., Yin, Z., Li, L., and Wang, Z. (2025). Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease. Signal Transduct. Target. Ther. 10: 254, https:\/\/doi.org\/10.1038\/s41392-025-02332-6.","DOI":"10.1038\/s41392-025-02332-6"},{"key":"2026111114033354246_j_hsz-2025-0251_ref_036","doi-asserted-by":"crossref","unstructured":"Chioni, A.M. and Grose, R. (2012). FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. 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