XPNPEP3

Xaa-Pro aminopeptidase 3, also known as aminopeptidase P3, is an enzyme that in humans is encoded by the XPNPEP3 gene. ^{[1] [2]} XPNPEP3 localizes to mitochondria in renal cells and to kidney tubules in a cell type-specific pattern. Mutations in XPNPEP3 gene have been identified as a cause of a nephronophthisis-like disease. ^[2]

Structure

Gene

The XPNPEP3 gene is located at chromosome 22q13.2, consisting of 12 exons. Two splice variants of XPNPEP3, APP3m and APP3c, exist in mitochondria and cytosol, respectively. ^{[3] [4]}

Protein

APP3m has an N-terminal mitochondrial-targeting sequence (MTS) domain importing APP3m into mitochondria, where the domain is removed proteolytically and APP3m functions as a 51-kDa mature protein. By contrast, APP3c, lacks the MTS and is expressed in the cytosol. ^[3] Arginine in MTS is required for mitochondrial transport. ^[5]

Function

XPNPEP3 belongs to a family of X-pro-aminopeptidases (EC 3.4.11.9) that utilize a metal cofactor and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. ^[4] It has been found that upon tumor necrosis factor stimulation, XPNPEP3 is released from mitochondria. XPNPEP3 is a new member of the TNF-TNFR2 signaling complex and plays a role in the transduction mechanism of TNFR2 signal which activates both JNK1 and JNK2 pathways. It is also observed that cell death increases upon downregulation of XPNPEP3, suggesting XPNPEP3 exerts an anti-apoptotic function. ^[3] Deletion of icp55, the S. cerevisiae ortholog of XPNPEP3, increases the proteolytic rate of its substrates through a protein degradation pathway characterized by the N-end rule. ^{[6] [7]}

Clinical significance

Mutations in the XPNPEP3 gene are associated with ciliopathy. ^[8] Recessive mutations in XPNPEP3 gene has been identified as a cause of a nephronophthisis-like disease, characterized by renal interstitial infiltration with fibrosis, tubular atrophy with basement membrane disruption, and cyst development at the corticomedullary renal border. ^[9] Phenotypic variability might be ascribed to different degrees of loss of function for the 2 different homozygous XPNPEP3 alleles. ^[2] The ciliary phenotypes unmasked by loss of XPNPEP3 might arise from the loss of XPNPEP3-dependent processing of ciliary proteins.

Interactions

• NPHP6/CEP290 ^{[10] [11]}
• TNF ^[3]

References

1. "Entrez Gene: X-prolyl aminopeptidase (aminopeptidase P) 3".
2. O'Toole JF, Liu Y, Davis EE, et al. (March 2010). "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy". J. Clin. Invest. 120 (3): 791–802. doi:10.1172/JCI40076. PMC   2827951 . PMID   20179356.
3. Inoue, Masaki; Kamada, Haruhiko; Abe, Yasuhiro; Higashisaka, Kazuma; Nagano, Kazuya; Mukai, Yohei; Yoshioka, Yasuo; Tsutsumi, Yasuo; Tsunoda, Shin-Ichi (2015-02-15). "Aminopeptidase P3, a new member of the TNF-TNFR2 signaling complex, induces phosphorylation of JNK1 and JNK2". Journal of Cell Science. 128 (4): 656–669. doi: 10.1242/jcs.149385 . ISSN   1477-9137. PMID   25609706.
4. Erşahin, C; Szpaderska, AM; Orawski, AT; Simmons, WH (15 March 2005). "Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractions". Archives of Biochemistry and Biophysics. 435 (2): 303–10. doi:10.1016/j.abb.2004.12.023. PMID   15708373.
5. Whatcott, Clifford J.; Meyer-Ficca, Mirella L.; Meyer, Ralph G.; Jacobson, Myron K. (2009-12-10). "A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence". Experimental Cell Research. 315 (20): 3477–3485. doi:10.1016/j.yexcr.2009.04.005. ISSN   1090-2422. PMC   2787692 . PMID   19389396.
6. Weller, Michael (2010-10-01). "Chemotherapy for low-grade gliomas: When? How? How long?". Neuro-Oncology. 12 (10): 1013. doi:10.1093/neuonc/noq137. ISSN   1522-8517. PMC   3018930 . PMID   20861092.
7. Varshavsky, Alexander (2011-08-01). "The N-end rule pathway and regulation by proteolysis". Protein Science. 20 (8): 1298–1345. doi:10.1002/pro.666. ISSN   1469-896X. PMC   3189519 . PMID   21633985.
8. Hurd TW, Hildebrandt F (2011). "Mechanisms of nephronophthisis and related ciliopathies". Nephron Exp. Nephrol. 118 (1): e9 –e14. doi:10.1159/000320888. PMC   2992643 . PMID   21071979.
9. Hildebrandt, F; Zhou, W (June 2007). "Nephronophthisis-associated ciliopathies". Journal of the American Society of Nephrology. 18 (6): 1855–71. doi: 10.1681/asn.2006121344 . PMID   17513324.
10. Khanna, Hemant; Davis, Erica E.; Murga-Zamalloa, Carlos A.; Estrada-Cuzcano, Alejandro; Lopez, Irma; den Hollander, Anneke I.; Zonneveld, Marijke N.; Othman, Mohammad I.; Waseem, Naushin (2009-06-01). "A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies". Nature Genetics. 41 (6): 739–745. doi:10.1038/ng.366. ISSN   1546-1718. PMC   2783476 . PMID   19430481.
11. Baala, Lekbir; Audollent, Sophie; Martinovic, Jéléna; Ozilou, Catherine; Babron, Marie-Claude; Sivanandamoorthy, Sivanthiny; Saunier, Sophie; Salomon, Rémi; Gonzales, Marie (2007-07-01). "Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome". American Journal of Human Genetics. 81 (1): 170–179. doi:10.1086/519494. ISSN   0002-9297. PMC   1950929 . PMID   17564974.

Further reading

• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Collins JE, Wright CL, Edwards CA, et al. (2004). "A genome annotation-driven approach to cloning the human ORFeome". Genome Biol. 5 (10) R84. doi: 10.1186/gb-2004-5-10-r84 . PMC   545604 . PMID   15461802.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Dunham I, Shimizu N, Roe BA, et al. (1999). "The DNA sequence of human chromosome 22". Nature. 402 (6761): 489–95. Bibcode:1999Natur.402..489D. doi: 10.1038/990031 . PMID   10591208.
• Bouwmeester T, Bauch A, Ruffner H, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID   14743216. S2CID   11683986.
• Barbe L, Lundberg E, Oksvold P, et al. (2008). "Toward a confocal subcellular atlas of the human proteome". Mol. Cell. Proteomics. 7 (3): 499–508. doi: 10.1074/mcp.M700325-MCP200 . PMID   18029348.