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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 an nephronophthisis-like disease.[2]



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]


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]


XPNPEP3 belongs to a family of X-pro-aminopeptidases (EC 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[edit]

Mutations in the XPNPEP3 gene are associated with ciliopathy.[8] Recessive mutations in XPNPEP3 gene has been identified as a cause of an 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.



  1. ^ "Entrez Gene: X-prolyl aminopeptidase (aminopeptidase P) 3". 
  2. ^ a b c 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 2827951Freely accessible. PMID 20179356. 
  3. ^ a b c d 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. ^ a b 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 2787692Freely accessible. 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 3018930Freely accessible. PMID 20861092. 
  7. ^ Varshavsky, Alexander (2011-08-01). "The N-end rule pathway and regulation by proteolysis". Protein Science: A Publication of the Protein Society. 20 (8): 1298–1345. doi:10.1002/pro.666. ISSN 1469-896X. PMC 3189519Freely accessible. 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 2992643Freely accessible. PMID 21071979. 
  9. ^ Hildebrandt, F; Zhou, W (June 2007). "Nephronophthisis-associated ciliopathies.". Journal of the American Society of Nephrology : JASN. 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 2783476Freely accessible. 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 1950929Freely accessible. PMID 17564974. 

Further reading[edit]