DPP9

DPP9
Identifiers
Aliases	DPP9 , DP9, DPLP9, DPRP-2, DPRP2, dipeptidyl peptidase 9, DPP IX
External IDs	OMIM: 608258; MGI: 2443967; HomoloGene: 16385; GeneCards: DPP9; OMA:DPP9 - orthologs
Gene location (Human) Chr. Chromosome 19 (human) [1] Band 19p13.3 Start 4,675,224 bp [1] End 4,724,673 bp [1]
Gene location (Mouse) Chr. Chromosome 17 (mouse) [2] Band 17|17 D Start 56,493,807 bp [2] End 56,525,905 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle muscle of thigh right lobe of liver granulocyte pancreatic ductal cell appendix upper lobe of left lung mucosa of transverse colon epithelium of colon apex of heart Top expressed in interventricular septum islet of Langerhans muscle of thigh internal carotid artery Rostral migratory stream lacrimal gland knee joint external carotid artery primary visual cortex skeletal muscle tissue More reference expression data BioGPS n/a
Gene ontology Molecular function peptidase activity serine-type peptidase activity aminopeptidase activity hydrolase activity identical protein binding Cellular component nucleus cytoplasm cytosol Biological process proteolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 91039 224897 Ensembl ENSG00000142002 ENSMUSG00000001229 UniProt Q86TI2 Q8BVG4 RefSeq (mRNA) NM_139159 NM_001365987 NM_172624 NM_001360284 RefSeq (protein) NP_631898 NP_001352916 NP_766212 NP_001347213 Location (UCSC) Chr 19: 4.68 – 4.72 Mb Chr 17: 56.49 – 56.53 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the DPP9 gene. ^[5]

Function

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]

Animal studies

Genetic analysis of knockout alleles of DPP9 in mice and zebrafish showed a severe phenotype that could be rescued by mutation of NLPR1. ^[9]

Clinical significance

Mutations in NLRP1 that block DPP9 interaction lead to a rare Mendelian condition called Autoinflammation with Arthritis and Dyskeratosis ^{[10] [11]} 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. ^[9]

This gene has also been linked to severe COVID-19. ^[12]

References

1. GRCh38: Ensembl release 89: ENSG00000142002 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001229 – 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. "Entrez Gene: DPP9 dipeptidyl-peptidase 9".
6. 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.
7. 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.
8. Sharif H, Hollingsworth LR, Griswold AR, Hsiao JC, Wang Q, Bachovchin DA, et al. (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.
9. Harapas CR, Robinson KS, Lay K, Wong J, Moreno Traspas R, Nabavizadeh N, et al. (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 . PMC   9844213 . PMID   36112693.
10. "Autoinflammation With Arthritis and Dyskeratosis; AIADK". Online Mendelian Inheritance in Man. 617388.
11. 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.
12. Ferreira LC, Gomes CE, Rodrigues-Neto JF, Jeronimo SM (December 2022). "Genome-wide association studies of COVID-19: Connecting the dots". Infection, Genetics and Evolution. 106: 105379. Bibcode:2022InfGE.10605379F. doi:10.1016/j.meegid.2022.105379. PMC   9584840 . PMID   36280088.

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, et al. (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, et al. (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, et al. (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.