GZMK

GZMK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MZA, 1MZD
Identifiers
Aliases	GZMK , TRYP2, granzyme K
External IDs	OMIM: 600784; MGI: 1298232; HomoloGene: 20485; GeneCards: GZMK; OMA:GZMK - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5q11.2 Start 55,024,256 bp [1] End 55,034,570 bp [1]
Gene location (Mouse) Chr. Chromosome 13 (mouse) [2] Band 13|13 D2.2 Start 113,308,142 bp [2] End 113,362,442 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lymph node granulocyte spleen blood appendix testicle gallbladder trabecular bone epithelium of nasopharynx thymus Top expressed in tail of embryo Region II of hippocampus proper submandibular gland supramammillary nucleus medial amygdaloid nucleus CA3 field central amygdaloid nucleus blood gastrula lymph node More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase activity serine-type peptidase activity hydrolase activity serine-type endopeptidase activity Cellular component extracellular region Biological process proteolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3003 14945 Ensembl ENSG00000113088 ENSMUSG00000042385 UniProt P49863 O35205 RefSeq (mRNA) NM_002104 NM_008196 RefSeq (protein) NP_002095 NP_032222 Location (UCSC) Chr 5: 55.02 – 55.03 Mb Chr 13: 113.31 – 113.36 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Granzyme K (GrK) is a protein that is encoded by the GZMK gene on chromosome 5 in humans. ^{[5] [6]} Granzymes are a family of serine proteases which have various intracellular and extracellular roles. GrK is found in granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and is traditionally described as being cytotoxic towards targeted foreign, infected, or cancerous cells. NK cells and CTLs can induce apoptosis through the granule secretory pathway, which involves the secretion of granzymes along with perforin at immunological synapses.

Intracellularly, GrK may cleave a variety of substrates, such as the nucleosome assembly protein (NAP), ^[7] HMG2, ^[7] and Ape1 ^[8] in the ER-associated SET complex, along with other targets that have downstream cytotoxic effects. Compared to in vitro studies of GrK cytotoxicity in rats and humans, in vitro mouse studies show no cytotoxic potential in the absence of perforin, making the role of GrK controversial. ^{[9] [10]} In vitro studies show potential extracellular targets for GrK such as the cleavage and activation of protease activated receptors (PAR)-1 ^{[11] [12]} and PAR-2. ^[13] Grk binds lipopolysaccharides (LPS) in vitro separately from GrK's catalytic activity. ^[14] Both PAR and LPS activation by GrK induce cytokine production in human in vitro studies.

GrK is important in bacterial and viral ^[15] infection control. GrK-expressing CD8+ T cells may be associated with inflammation and aging. ^[16]

GrK may also be able to independently activate the complement system via cleavage of C2 and C4. ^[17]

References

1. GRCh38: Ensembl release 89: ENSG00000113088 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000042385 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Przetak MM, Yoast S, Schmidt BF (May 1995). "Cloning of cDNA for human granzyme 3". FEBS Letters. 364 (3): 268–271. doi:10.1016/0014-5793(95)00407-Z. PMID   7758581. S2CID   29315976.
6. "Entrez Gene: GZMK granzyme K (granzyme 3; tryptase II)".
7. Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H, Hou Q, Liu H, Fan Z (March 2007). "Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells". Cell Death and Differentiation. 14 (3): 489–499. doi:10.1038/sj.cdd.4402040. PMID   17008916. S2CID   6044972.
8. Guo Y, Chen J, Zhao T, Fan Z (April 2008). "Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity". Molecular Immunology. 45 (8): 2225–2235. doi:10.1016/j.molimm.2007.11.020. PMID   18179823.
9. Susanto O, Trapani JA, Brasacchio D (December 2012). "Controversies in granzyme biology". Tissue Antigens. 80 (6): 477–487. doi:10.1111/tan.12014. PMID   23137319.
10. Bouwman AC, van Daalen KR, Crnko S, ten Broeke T, Bovenschen N (2021). "Intracellular and Extracellular Roles of Granzyme K". Frontiers in Immunology. 12 677707. doi: 10.3389/fimmu.2021.677707 . ISSN   1664-3224. PMC   8129556 . PMID   34017346.
11. Cooper DM, Pechkovsky DV, Hackett TL, Knight DA, Granville DJ (2011-06-30). "Granzyme K activates protease-activated receptor-1". PLOS ONE. 6 (6) e21484. Bibcode:2011PLoSO...621484C. doi: 10.1371/journal.pone.0021484 . PMC   3128063 . PMID   21760880.
12. Sharma M, Merkulova Y, Raithatha S, Parkinson LG, Shen Y, Cooper D, Granville DJ (May 2016). "Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1". The FEBS Journal. 283 (9): 1734–1747. doi: 10.1111/febs.13699 . PMID   26936634. S2CID   21180451.
13. Kaiserman D, Zhao P, Rowe CL, Leong A, Barlow N, Joeckel LT, Hitchen C, Stewart SE, Hollenberg MD, Bunnett N, Suhrbier A, Bird PI (2022-07-01). "Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2". PLOS ONE. 17 (7) e0270584. Bibcode:2022PLoSO..1770584K. doi: 10.1371/journal.pone.0270584 . PMC   9321427 . PMID   35881628.
14. Wensink AC, Kemp V, Fermie J, García Laorden MI, van der Poll T, Hack CE, Bovenschen N (April 2014). "Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes". Proceedings of the National Academy of Sciences of the United States of America. 111 (16): 5974–5979. Bibcode:2014PNAS..111.5974W. doi: 10.1073/pnas.1317347111 . PMC   4000831 . PMID   24711407.
15. Zhong C, Li C, Wang X, Toyoda T, Gao G, Fan Z (May 2012). "Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin α1/β dimer of infected host cells". Cell Death and Differentiation. 19 (5): 882–890. doi:10.1038/cdd.2011.178. PMC   3321629 . PMID   22139131.
16. Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, Brioschi S, Shchukina I, Kerndl M, Bambouskova M, Yao Z, Laha A, Zaitsev K, Burdess S, Gillfilan S, Stewart SA, Colonna M, Artyomov MN (January 2021). "Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK⁺ CD8⁺ T Cells as Conserved Hallmark of Inflammaging". Immunity. 54 (1): 99–115.e12. doi: 10.1016/j.immuni.2020.11.005 . PMID   33271118. S2CID   227282306.
17. Donado CA, Theisen E, Zhang F, Nathan A, Fairfield ML, Rupani KV, Jones D, Johannes KP, Raychaudhuri S, Dwyer DF, Jonsson AH, Brenner MB (May 2025). "Granzyme K activates the entire complement cascade" . Nature. 641 (8061): 211–221. doi:10.1038/s41586-025-08713-9. ISSN   1476-4687 . Retrieved 8 September 2025.

Further reading

• Smyth MJ, O'Connor MD, Trapani JA (November 1996). "Granzymes: a variety of serine protease specificities encoded by genetically distinct subfamilies". Journal of Leukocyte Biology. 60 (5): 555–562. doi:10.1002/jlb.60.5.555. PMID   8929545. S2CID   19732623.
• Shi L, Kam CM, Powers JC, Aebersold R, Greenberg AH (December 1992). "Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions". The Journal of Experimental Medicine. 176 (6): 1521–1529. doi:10.1084/jem.176.6.1521. PMC   2119451 . PMID   1460416.
• Hameed A, Lowrey DM, Lichtenheld M, Podack ER (November 1988). "Characterization of three serine esterases isolated from human IL-2 activated killer cells". Journal of Immunology. 141 (9): 3142–3147. doi:10.4049/jimmunol.141.9.3142. PMID   3262682.
• Baker E, Sayers TJ, Sutherland GR, Smyth MJ (1994). "The genes encoding NK cell granule serine proteases, human tryptase-2 (TRYP2) and human granzyme A (HFSP), both map to chromosome 5q11-q12 and define a new locus for cytotoxic lymphocyte granule tryptases". Immunogenetics. 40 (3): 235–237. doi:10.1007/BF00167085. PMID   8039831. S2CID   37615055.
• Sayers TJ, Lloyd AR, McVicar DW, O'Connor MD, Kelly JM, Carter CR, Wiltrout TA, Wiltrout RH, Smyth MJ (May 1996). "Cloning and expression of a second human natural killer cell granule tryptase, HNK-Tryp-2/granzyme 3". Journal of Leukocyte Biology. 59 (5): 763–768. doi:10.1002/jlb.59.5.763. PMID   8656064. S2CID   18065724.
• Hink-Schauer C, Estébanez-Perpiñá E, Wilharm E, Fuentes-Prior P, Klinkert W, Bode W, Jenne DE (December 2002). "The 2.2-A crystal structure of human pro-granzyme K reveals a rigid zymogen with unusual features". The Journal of Biological Chemistry. 277 (52): 50923–50933. doi: 10.1074/jbc.M207962200 . PMID   12384499.
• Fajardo I, Pejler G (February 2003). "Formation of active monomers from tetrameric human beta-tryptase". The Biochemical Journal. 369 (Pt 3): 603–610. doi:10.1042/BJ20021418. PMC   1223112 . PMID   12387726.
• Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H, Hou Q, Liu H, Fan Z (March 2007). "Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells". Cell Death and Differentiation. 14 (3): 489–499. doi:10.1038/sj.cdd.4402040. PMID   17008916. S2CID   6044972.
• Zhao T, Zhang H, Guo Y, Fan Z (April 2007). "Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death". The Journal of Biological Chemistry. 282 (16): 12104–12111. doi: 10.1074/jbc.M611006200 . PMID   17308307.
• Rucevic M, Fast LD, Jay GD, Trespalcios FM, Sucov A, Siryaporn E, Lim YP (May 2007). "Altered levels and molecular forms of granzyme k in plasma from septic patients". Shock. 27 (5): 488–493. doi: 10.1097/01.shk.0000246905.24895.e5 . PMID   17438453. S2CID   525904.