A new member at the table: Granzyme K as a lymphocyte-born complement initiator

Manoj Kumar Pandey

Clinical and Translational Discovery ›› 2025, Vol. 5 ›› Issue (4) : e70069

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Clinical and Translational Discovery ›› 2025, Vol. 5 ›› Issue (4) : e70069 DOI: 10.1002/ctd2.70069
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A new member at the table: Granzyme K as a lymphocyte-born complement initiator

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Manoj Kumar Pandey. A new member at the table: Granzyme K as a lymphocyte-born complement initiator. Clinical and Translational Discovery, 2025, 5(4): e70069 DOI:10.1002/ctd2.70069

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References

[1]

Kemper C, Ferreira VP, Paz JT, Holers VM, Lionakis MS, Alexander JJ. Complement: the road less traveled. J Immunol. 2023; 210(2): 119-125.

[2]

King BC, Blom AM. Intracellular complement: evidence, definitions, controversies, and solutions. Immunol Rev. 2023; 313(1): 104-119.

[3]

Krisinger MJ, Goebeler V, Lu Z, et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood. 2012; 120(8): 1717-1725.

[4]

Arbore G, Kemper C, Kolev M. Intracellular complement—the complosome—in immune cell regulation. Mol Immunol. 2017; 89: 2-9.

[5]

Reichhardt MP, Meri S. Intracellular complement activation—an alarm raising mechanism?. Semin Immunol. 2018; 38: 54-62.

[6]

Prasad RR, Kumar S, Zhang H, et al. An intracellular complement system drives metabolic and proinflammatory reprogramming of vascular fibroblasts in pulmonary hypertension. JCI Insight. 2025; 10(6):e184141.

[7]

Irmscher S, Döring N, Halder LD, et al. Kallikrein cleaves C3 and activates complement. J Innate Immun. 2018; 10(2): 94-105.

[8]

Bekassy Z, Lopatko Fagerström I, Bader M, Karpman D. Crosstalk between the renin–angiotensin, complement and kallikrein–kinin systems in inflammation. Nat Rev Immunol. 2022; 22(7): 411-428.

[9]

King BC, Blom AM. Intracellular complement and immunometabolism: the advantages of compartmentalization. Eur J Immunol. 2024; 54(8):2350813.

[10]

Donado CA, Theisen E, Zhang F, et al. Granzyme K activates the entire complement cascade. Nature. 2025; 641(8061): 211-221.

[11]

Grossman WJ, Revell PA, Lu ZH, Johnson H, Bredemeyer AJ, Ley TJ. The orphan granzymes of humans and mice. Curr Opin Immunol. 2003; 15(5): 544-552.

[12]

Van Daalen KR, Reijneveld JF, Bovenschen N. Modulation of inflammation by extracellular granzyme A. Front Immunol. 2020; 11: 931.

[13]

van Domselaar R, Bovenschen N. Cell death-independent functions of granzymes: hit viruses where it hurts. Rev Med Virol. 2011; 21(5): 301-314.

[14]

Wensink AC, Hack CE, Bovenschen N. Granzymes regulate proinflammatory cytokine responses. J Immunol. 2015; 194(2): 491-497.

[15]

Bovenschen N, Spijkers SN, Wensink AC, Schellens IM, van Domselaar R, van Baarle D. Elevated granzyme M-expressing lymphocytes during cytomegalovirus latency and reactivation after allogeneic stem cell transplantation. Clin Immunol. 2014; 150(1): 1-11.

[16]

Van Domselaar R, De Poot S, Remmerswaal E, Lai K, Ten Berge I, Bovenschen N. Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication. Cell Death Differ. 2013; 20(3): 419-429.

[17]

van Domselaar R, Quadir R, van der Made AM, Broekhuizen R, Bovenschen N. All human granzymes target hnRNP K that is essential for tumor cell viability. J Biol Chem. 2012; 287(27): 22854-22864.

[18]

Bade B, Boettcher HE, Lohrmann J, et al. Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes. Int Immunol. 2005; 17(11): 1419-1428.

[19]

Bratke K, Kuepper M, Bade B, Virchow Jr JC, Luttmann W. Differential expression of human granzymes A, B, and K in natural killer cells and during CD8+ T cell differentiation in peripheral blood. Eur J Immunol. 2005; 35(9): 2608-2616.

[20]

Bade B, Lohrmann J, ten Brinke A, et al. Detection of soluble human granzyme K in vitro and in vivo. Eur J Immunol. 2005; 35(10): 2940-2948.

[21]

Hirata Y, Inagaki H, Shimizu T, Kawada T. Substrate specificity of human granzyme 3: analyses of the P3-P2-P1 triplet using fluorescence resonance energy transfer substrate libraries. BioSci Trends. 2014; 8(2): 126-131.

[22]

Hink-Schauer C, Estébanez-Perpiná E, Wilharm E, et al. The 2.2-Å crystal structure of human pro-granzyme K reveals a rigid zymogen with unusual features. J Biol Chem. 2002; 277(52): 50923-50933.

[23]

Hameed A, Lowrey DM, Lichtenheld M, Podack ER. Characterization of three serine esterases isolated from human IL-2 activated killer cells. J Immunol. 1988; 141(9): 3142-3147.

[24]

Hirata Y, Inagaki H, Kawada T. Recombinant human progranzyme 3 expressed in Escherichia coli for analysis of its activation mechanism. Microbiol Immunol. 2010; 54(2): 98-104.

[25]

Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008; 26(1): 389-420.

[26]

Bovenschen N, Quadir R, van den Berg AL, et al. Granzyme K displays highly restricted substrate specificity that only partially overlaps with granzyme A. J Biol Chem. 2009; 284(6): 3504-3512.

[27]

Plasman K, Demol H, Bird PI, Gevaert K, Van Damme P. Substrate specificities of the granzyme tryptases A and K. J Proteome Res. 2014; 13(12): 6067-6077.

[28]

Jonsson AH, Zhang F, Dunlap G, et al. Granzyme K(+) CD8 T cells form a core population in inflamed human tissue. Sci Transl Med. 2022; 14(649):eabo0686.

[29]

Duquette D, Harmon C, Zaborowski A, et al. Human Granzyme K is a feature of innate T cells in blood, tissues, and tumors, responding to cytokines rather than TCR stimulation. J Immunol. 2023; 211(4): 633-647.

[30]

Lan F, Li J, Miao W, et al. GZMK-expressing CD8(+) T cells promote recurrent airway inflammatory diseases. Nature. 2025; 638(8050): 490-498.

[31]

Gao Y, Liu R, Shi J, et al. Clonal GZMK(+)CD8(+) T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. EBioMedicine. 2025; 112:105535.

[32]

Turner CT. Pro-inflammatory granzyme K contributes extracellularly to disease. Front Immunol. 2025; 16: 2025.

[33]

Häcker U, Nybakken K, Perrimon N. Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol. 2005; 6(7): 530-541.

[34]

Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007; 446(7139): 1030-1037.

[35]

Wuillemin WA, Velthuis H, Lubbers YT, de Ruig CP, Eldering E, Hack CE. Potentiation of C1 inhibitor by glycosaminoglycans: dextran sulfate species are effective inhibitors of in vitro complement activation in plasma. J Immunol. 1997; 159(4): 1953-1960.

[36]

Sahu A, Pangburn MK. Identification of multiple sites of interaction between heparin and the complement system. Mol Immunol. 1993; 30(7): 679-684.

[37]

Presanis JS, Hajela K, Ambrus G, Gál P, Sim RB. Differential substrate and inhibitor profiles for human MASP-1 and MASP-2. Mol Immunol. 2004; 40(13): 921-929.

[38]

Diamond MS, Alon R, Parkos CA, Quinn MT, Springer TA. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol. 1995; 130(6): 1473-1482.

[39]

Vorup-Jensen T, Chi L, Gjelstrup LC, et al. Binding between the Integrin αXβ2 (CD11c/CD18) and Heparin *. J Biol Chem. 2007; 282(42): 30869-30877.

[40]

Richardson KC, Jung K, Pardo J, Turner CT, Granville DJ. Noncytotoxic roles of granzymes in health and disease. Physiology. 2022; 37(6): 323-348.

[41]

Hillmen P, Muus P, Röth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013; 162(1): 62-73.

[42]

Kanakura Y, Ohyashiki K, Shichishima T, et al. Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial. Int J Hematol. 2013; 98: 406-416.

[43]

Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open. 2013; 3(11):e003573.

[44]

Rondeau E, Cataland SR, Al-Dakkak I, Miller B, Webb NJ, Landau D. Eculizumab safety: five-year experience from the global atypical hemolytic uremic syndrome registry. Kidney Int Rep. 2019; 4(11): 1568-1576.

[45]

Socié G, Caby-Tosi MP, Marantz JL, et al. Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis. Br J Haematol. 2019; 185(2): 297-310.

[46]

Nolfi-Donegan D, Konar M, Vianzon V, et al. Fatal nongroupable Neisseria meningitidis disease in vaccinated patient receiving eculizumab. Emerg Infect Dis. 2018; 24(8): 1561.

[47]

Graciaa SH, Graciaa DS, Yildirim I, Chonat S. Risk of disseminated gonococcal infections with terminal complement blockade. J Pediatr Hematol Oncol. 2022; 44(2): e493-e495.

[48]

Garred P, Tenner AJ, Mollnes TE. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021; 73(2): 792-827.

[49]

Heesterbeek Dani AC, Angelier Mathieu L, Harrison Richard A, Rooijakkers Suzan HM. Complement and bacterial infections: from molecular mechanisms to therapeutic applications. J Innate Immun. 2018; 10(5-6): 455-464.

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2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

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