DPP9 explained

Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the DPP9 gene.^[1]

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. 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.^{[2] [3]} A similar mechanism allows DPP9 to regulate the CARD8 inflammasome.^[4]

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^{[5] [6]} 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.^[7] 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.

Further reading

• Olsen C, Wagtmann N . Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV . Gene . 299 . 1–2 . 185–193 . October 2002 . 12459266 . 10.1016/S0378-1119(02)01059-4 .
• Ajami K, Abbott CA, Obradovic M, Gysbers V, Kähne T, McCaughan GW, Gorrell MD . Structural requirements for catalysis, expression, and dimerization in the CD26/DPIV gene family . Biochemistry . 42 . 3 . 694–701 . January 2003 . 12534281 . 10.1021/bi026846s .
• Qi SY, Riviere PJ, Trojnar J, Junien JL, Akinsanya KO . 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 . July 2003 . 12662155 . 1223468 . 10.1042/BJ20021914 .
• Ajami K, Abbott CA, McCaughan GW, Gorrell MD . 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 . July 2004 . 15245913 . 10.1016/j.bbaexp.2004.03.010 .
• Ogasawara W, Tanaka C, Suzuki M, Kobayashi G, Ogawa Y, Okada H, Morikawa Y . 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 . June 2005 . 15866709 . 10.1016/j.pep.2004.10.027 .
• Bjelke JR, Christensen J, Nielsen PF, Branner S, Kanstrup AB, Wagtmann N, Rasmussen HB . Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV . The Biochemical Journal . 396 . 2 . 391–399 . June 2006 . 16475979 . 1462722 . 10.1042/BJ20060079 .
• Book: Yu DM, Wang XM, Ajami K, McCaughan GW, Gorrell MD . Dipeptidyl Aminopeptidases . DP8 and DP9 have extra-enzymatic roles in cell adhesion, migration and apoptosis . 575 . 63–72 . 2006 . 16700509 . 10.1007/0-387-32824-6_7 . 978-0-387-29058-4 . Advances in Experimental Medicine and Biology .
• Yu DM, Wang XM, McCaughan GW, Gorrell MD . 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 . June 2006 . 16704418 . 10.1111/j.1742-4658.2006.05253.x . 19075840 . free .

Notes and References

1. Web site: Entrez Gene: DPP9 dipeptidyl-peptidase 9.
2. Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu H . 6 . DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation . Nature . 592 . 7856 . 778–783 . April 2021 . 33731932 . 8299537 . 10.1038/s41586-021-03350-4 . 2021Natur.592..778H .
3. Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, Wu B, Zhong F, Chai J . 6 . Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 . Nature . 592 . 7856 . 773–777 . April 2021 . 33731929 . 8081665 . 10.1038/s41586-021-03320-w . 2021Natur.592..773H .
4. Sharif H, Hollingsworth LR, Griswold AR, Hsiao JC, Wang Q, Bachovchin DA, Wu H . Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment . Immunity . 54 . 7 . 1392–1404.e10 . July 2021 . 34019797 . 8423358 . 10.1016/j.immuni.2021.04.024 .
5. Web site: Autoinflammation With Arthritis and Dyskeratosis; AIADK . 617388 . Online Mendelian Inheritance in Man .
6. Zhong FL, Robinson K, Teo DE, Tan KY, Lim C, Harapas CR, Yu CH, Xie WH, Sobota RM, Au VB, Hopkins R, D'Osualdo A, Reed JC, Connolly JE, Masters SL, Reversade B . 6 . 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 . December 2018 . 30291141 . 6295727 . 10.1074/jbc.RA118.004350 . free .
7. DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling . Science Immunology . 7 . 75 . September 2022 . 36112693 . 10.1126/sciimmunol.abi4611 . 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 . eabi4611 . 9844213 . 10754/681562 . free .