DPP9
Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the DPP9 gene.[5]
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| Aliases | DPP9, DP9, DPLP9, DPRP-2, DPRP2, dipeptidyl peptidase 9, DPP IX | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608258 MGI: 2443967 HomoloGene: 16385 GeneCards: DPP9 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Although the activity of this protein is similar to that of dipeptidyl peptidase 4 (DPP4), it does not appear to be membrane bound.
In general, dipeptidyl peptidases appear to be involved in the regulation of the activity of their substrates and have been linked to a variety of diseases including type 2 diabetes, obesity and cancer. Several transcript variants of this gene have been described but not fully characterized.[5] More specifically, DPP9 interacts with the NLRP1 protein and affects the level of activation of the NLRP1 inflammasome. This function involves binding to a complex of full-length NLRP1 and a proinflammatory fragment of NLRP1 after activation by autocleavage.[6][7] A similar mechanism allows DPP9 to regulate the CARD8 inflammasome.[8]
This gene has also been linked to severe COVID-19.
Medical Genetics
Mutations in NLRP1 that block DPP9 interaction lead to a rare Mendelian condition called Autoinflammation with Arthritis and Dyskeratosis[9][10] A homozygous recessive syndrome dubbed Hatipoğlu syndrome is attributed to mutations in DPP9 with a phenotype of failure to thrive, skin manifestations, pancytopenia, and susceptibility to infections.[11] Genetic analysis of knockout alleles of DPP9 in mice and zebrafish showed a severe phenotype that could be rescued by mutation of NLPR1 in the same report.
References
- GRCh38: Ensembl release 89: ENSG00000142002 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000001229 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Entrez Gene: DPP9 dipeptidyl-peptidase 9".
- Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, et al. (April 2021). "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation". Nature. 592 (7856): 778–783. Bibcode:2021Natur.592..778H. doi:10.1038/s41586-021-03350-4. PMC 8299537. PMID 33731932.
- Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, et al. (April 2021). "Structural and biochemical mechanisms of NLRP1 inhibition by DPP9". Nature. 592 (7856): 773–777. Bibcode:2021Natur.592..773H. doi:10.1038/s41586-021-03320-w. PMC 8081665. PMID 33731929.
- Sharif H, Hollingsworth LR, Griswold AR, Hsiao JC, Wang Q, Bachovchin DA, Wu H (July 2021). "Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment". Immunity. 54 (7): 1392–1404.e10. doi:10.1016/j.immuni.2021.04.024. PMC 8423358. PMID 34019797.
- "Autoinflammation With Arthritis and Dyskeratosis; AIADK". Online Mendelian Inheritance in Man. 617388.
- Zhong FL, Robinson K, Teo DE, Tan KY, Lim C, Harapas CR, et al. (December 2018). "Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding". The Journal of Biological Chemistry. 293 (49): 18864–18878. doi:10.1074/jbc.RA118.004350. PMC 6295727. PMID 30291141.
- Harapas, Cassandra R.; Robinson, Kim S.; Lay, Kenneth; Wong, Jasmine; Moreno Traspas, Ricardo; Nabavizadeh, Nasrin; Rass-Rothschild, Annick; Boisson, Bertrand; Drutman, Scott B.; Laohamonthonkul, Pawat; Bonner, Devon; Xiong, Jingwei Rachel; Gorrell, Mark D.; Davidson, Sophia; Yu, Chien-Hsiung; Fleming, Mark D.; Gudera, Jonas; Stein, Jerry; Ben-Harosh, Miriam; Groopman, Emily; Shimamura, Akiko; Tamary, Hannah; Kayserili, Hülya; Hatipoğlu, Nevin; Casanova, Jean-Laurent; Bernstein, Jonathan A.; Zhong, Franklin L.; Masters, Seth L.; Reversade, Bruno (September 2022). "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling". Science Immunology. 7 (75): eabi4611. doi:10.1126/sciimmunol.abi4611. hdl:10754/681562. PMID 36112693.
Further reading
- Olsen C, Wagtmann N (October 2002). "Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV". Gene. 299 (1–2): 185–193. doi:10.1016/S0378-1119(02)01059-4. PMID 12459266.
- Ajami K, Abbott CA, Obradovic M, Gysbers V, Kähne T, McCaughan GW, Gorrell MD (January 2003). "Structural requirements for catalysis, expression, and dimerization in the CD26/DPIV gene family". Biochemistry. 42 (3): 694–701. doi:10.1021/bi026846s. PMID 12534281.
- Qi SY, Riviere PJ, Trojnar J, Junien JL, Akinsanya KO (July 2003). "Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases". The Biochemical Journal. 373 (Pt 1): 179–189. doi:10.1042/BJ20021914. PMC 1223468. PMID 12662155.
- Ajami K, Abbott CA, McCaughan GW, Gorrell MD (July 2004). "Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1679 (1): 18–28. doi:10.1016/j.bbaexp.2004.03.010. PMID 15245913.
- Ogasawara W, Tanaka C, Suzuki M, Kobayashi G, Ogawa Y, Okada H, Morikawa Y (June 2005). "Isoforms of dipeptidyl aminopeptidase IV from Pseudomonas sp. WO24: role of the signal sequence and overexpression in Escherichia coli". Protein Expression and Purification. 41 (2): 241–251. doi:10.1016/j.pep.2004.10.027. PMID 15866709.
- Bjelke JR, Christensen J, Nielsen PF, Branner S, Kanstrup AB, Wagtmann N, Rasmussen HB (June 2006). "Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV". The Biochemical Journal. 396 (2): 391–399. doi:10.1042/BJ20060079. PMC 1462722. PMID 16475979.
- Yu DM, Wang XM, Ajami K, McCaughan GW, Gorrell MD (2006). "DP8 and DP9 have extra-enzymatic roles in cell adhesion, migration and apoptosis". Dipeptidyl Aminopeptidases. Advances in Experimental Medicine and Biology. Vol. 575. pp. 63–72. doi:10.1007/0-387-32824-6_7. ISBN 978-0-387-29058-4. PMID 16700509.
- Yu DM, Wang XM, McCaughan GW, Gorrell MD (June 2006). "Extraenzymatic functions of the dipeptidyl peptidase IV-related proteins DP8 and DP9 in cell adhesion, migration and apoptosis". The FEBS Journal. 273 (11): 2447–2460. doi:10.1111/j.1742-4658.2006.05253.x. PMID 16704418. S2CID 19075840.