XPNPEP3

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.{{Cite journal|last1=Inoue|first1=Masaki|last2=Kamada|first2=Haruhiko|last3=Abe|first3=Yasuhiro|last4=Higashisaka|first4=Kazuma|last5=Nagano|first5=Kazuya|last6=Mukai|first6=Yohei|last7=Yoshioka|first7=Yasuo|last8=Tsutsumi|first8=Yasuo|last9=Tsunoda|first9=Shin-Ichi|date=2015-02-15|title=Aminopeptidase P3, a new member of the TNF-TNFR2 signaling complex, induces phosphorylation of JNK1 and JNK2|journal=Journal of Cell Science|volume=128|issue=4|pages=656–669|doi=10.1242/jcs.149385|issn=1477-9137|pmid=25609706|doi-access=free}}{{cite journal|last1=Erşahin|first1=C|last2=Szpaderska|first2=AM|last3=Orawski|first3=AT|last4=Simmons|first4=WH|title=Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractions.|journal=Archives of Biochemistry and Biophysics|date=15 March 2005|volume=435|issue=2|pages=303–10|pmid=15708373|doi=10.1016/j.abb.2004.12.023}}

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. Arginine in MTS is required for mitochondrial transport.{{Cite journal|last1=Whatcott|first1=Clifford J.|last2=Meyer-Ficca|first2=Mirella L.|last3=Meyer|first3=Ralph G.|last4=Jacobson|first4=Myron K.|date=2009-12-10|title=A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence|journal=Experimental Cell Research|volume=315|issue=20|pages=3477–3485|doi=10.1016/j.yexcr.2009.04.005|issn=1090-2422|pmc=2787692|pmid=19389396}}

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. 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. 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.{{Cite journal|last=Weller|first=Michael|date=2010-10-01|title=Chemotherapy for low-grade gliomas: When? How? How long?|journal=Neuro-Oncology|volume=12|issue=10|pages=1013|doi=10.1093/neuonc/noq137|issn=1522-8517|pmc=3018930|pmid=20861092}}{{Cite journal|last=Varshavsky|first=Alexander|date=2011-08-01|title=The N-end rule pathway and regulation by proteolysis|journal=Protein Science|volume=20|issue=8|pages=1298–1345|doi=10.1002/pro.666|issn=1469-896X|pmc=3189519|pmid=21633985}}

Mutations in the XPNPEP3 gene are associated with ciliopathy.{{cite journal |vauthors=Hurd TW, Hildebrandt F | title = Mechanisms of nephronophthisis and related ciliopathies | journal = Nephron Exp. Nephrol. | volume = 118 | issue = 1 | pages = e9–e14 | year = 2011 | pmid = 21071979 | doi = 10.1159/000320888 | pmc=2992643}} 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.{{cite journal|last1=Hildebrandt|first1=F|last2=Zhou|first2=W|title=Nephronophthisis-associated ciliopathies.|journal=Journal of the American Society of Nephrology|date=June 2007|volume=18|issue=6|pages=1855–71|pmid=17513324|doi=10.1681/asn.2006121344|doi-access=free}} Phenotypic variability might be ascribed to different degrees of loss of function for the 2 different homozygous XPNPEP3 alleles. The ciliary phenotypes unmasked by loss of XPNPEP3 might arise from the loss of XPNPEP3-dependent processing of ciliary proteins.

• NPHP6/CEP290 {{Cite journal|last1=Khanna|first1=Hemant|last2=Davis|first2=Erica E.|last3=Murga-Zamalloa|first3=Carlos A.|last4=Estrada-Cuzcano|first4=Alejandro|last5=Lopez|first5=Irma|last6=den Hollander|first6=Anneke I.|last7=Zonneveld|first7=Marijke N.|last8=Othman|first8=Mohammad I.|last9=Waseem|first9=Naushin|date=2009-06-01|title=A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies|journal=Nature Genetics|volume=41|issue=6|pages=739–745|doi=10.1038/ng.366|issn=1546-1718|pmc=2783476|pmid=19430481}}{{Cite journal|last1=Baala|first1=Lekbir|last2=Audollent|first2=Sophie|last3=Martinovic|first3=Jéléna|last4=Ozilou|first4=Catherine|last5=Babron|first5=Marie-Claude|last6=Sivanandamoorthy|first6=Sivanthiny|last7=Saunier|first7=Sophie|last8=Salomon|first8=Rémi|last9=Gonzales|first9=Marie|date=2007-07-01|title=Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome|journal=American Journal of Human Genetics|volume=81|issue=1|pages=170–179|doi=10.1086/519494|issn=0002-9297|pmc=1950929|pmid=17564974}}
• TNF

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{{Proteases}}

{{Enzymes}}

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Category:EC 3.4.11

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