Disease relevance of ARTS-1

• In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n = 26), gestational choriocarcinoma (n = 8), and placental site trophoblastic tumor (n = 3) [1].
• In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms [1].
• We considered the hypothesis that genomic variants of the ALAP gene are associated with hypertension or individual variations in blood pressure [2].
• We generated ERAP1-deficient mice and analyzed cytotoxic responses upon infection with three viruses, including lymphocytic choriomeningitis virus, which causes vigorous T cell activation and is controlled by CTLs [3].
• This study examined the role of A-LAP in angiogenesis of human endometrial carcinoma [4].

Psychiatry related information on ARTS-1

• In September 2001, the author was invited by Dr. Wendy Makin (Macmillan Consultant in Palliative Care) and Andrea Sarginson (Volunteer Arts Worker) to introduce art therapy to the Christie Hospital as part of a postgraduate training course at the University of Sheffield [5].
• After the war, interest in Reflexology and Pavlov's theories slowly rose again, first through psychosomatic medicine and then in the 60's because of the works of such authors as Monserrat-Esteve, Rof Carballo and Colodrón. The progressive inclusion of psychology in the Schools of Philosophy and Arts after 1968 marked the beginning of a new era [6].

High impact information on ARTS-1

• ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum [7].
• Here we identify ERAAP, the aminopeptidase associated with antigen processing in the ER [7].
• Reducing the expression of ERAAP through RNA interference prevents the trimming of peptides for MHC class I molecules in the ER and greatly reduces the expression of MHC class I molecules on the cell surface [7].
• Furthermore, ERAAP-deficient cells presented many unstable and structurally unique peptide-MHC complexes, which elicited potent CD8(+) T cell and B cell responses [8].
• We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2 [9].

Chemical compound and disease context of ARTS-1

• This study investigated whether the expression of A-LAP, Ang II, angiotensin type I receptor (AT1R) and vascular endothelial growth factor (VEGF) correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma [10].
• METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 94 primary endometrial carcinomas were stained for A-LAP, AngII, AT1R and VEGF using each antibody [10].
• He was qualified in both Arts and Medicine and commenced his professional life as a Physiologist, became Professor of Pathology and led the study of immunity to infectious diseases [11].
• CONCLUSIONS: The ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy [12].

Biological context of ARTS-1

• A yeast two-hybrid screen of a human placenta cDNA library showed that NUCB2 (nucleobindin 2), via its helix-loop-helix domains, binds the ARTS-1 extracellular domain [13].
• Western blotting analysis showed that A-LAP was present in the endometrial tissue throughout the menstrual cycle [14].
• Adipocyte-derived leucine aminopeptidase (A-LAP, endoplasmic reticulum aminopeptidase ERAP1) is specialized to produce peptides presented on the class I major histocompatibility complex (MHC) by trimming epitopes to eight or nine residues, in addition to its enzymatic activity to degrade angiotensin II [14].
• The predicted A-LAP contains the HEXXH(X)18E consensus sequence, which is characteristic of the M1 family of zinc-metallopeptidases [15].
• When aminopeptidase activity of A-LAP was measured with various synthetic substrates, the enzyme revealed a preference for leucine, establishing that A-LAP is a novel leucine aminopeptidase with restricted substrate specificity [15].

Anatomical context of ARTS-1

• In vivo binding of membrane-associated ARTS-1 to TNFR1 was confirmed by coimmunoprecipitation experiments using human pulmonary epithelial and umbilical vein endothelial cells [16].
• Basal IL-1RII shedding is absent from ARTS-1 knockout cell lines, demonstrating that ARTS-1 is required for constitutive IL-1RII shedding [17].
• The goal of this study was to identify ARTS-1 binding partners that modulate TNFR1 release to the extracellular space [13].
• Here we analyzed the distribution of A-LAP in human cyclic endometrium [14].
• Subcellular localization of A-LAP, demonstrated by immunofluorescence, was ER in the cultured glandular epithelial cells [14].

Associations of ARTS-1 with chemical compounds

• ARTS-1 expression also enhances ionomycin-induced IL-1RII shedding [17].
• ERAP1 is inhibited by agents that block precursor trimming in ER vesicles and although it trimmed NH2-extended precursors, it spared presented peptides of 8 amino acid and less [18].
• Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin [1].
• Adipocyte-derived leucine aminopeptidase (ALAP) inactivates angiotensin II and/or generates bradykinin in the kidney, suggesting a possible role for ALAP in the regulation of blood pressure [2].
• Exploratory analysis of global power (sites F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4) revealed that ERAP increased during SH from time 1 to time 3 at all sites except Fz and Pz, whereas only one site (C4) revealed an increase during BL [19].

Physical interactions of ARTS-1

• We propose that formation of a TNFR1-ARTS-1 molecular complex represents a novel mechanism by which TNFR1 shedding is regulated [16].

Regulatory relationships of ARTS-1

• These data indicate that ARTS-1 is a multifunctional ectoprotein capable of binding to and promoting TNFR1 shedding [16].
• We conclude that the ability of ARTS-1 to enhance IL-1RII shedding represents a new mechanism by which IL-1-induced cellular events can be modulated [17].
• Overexpression of A-LAP attenuated Ang II-induced VEGF expression in HEC-1A cells [4].
• This study provides the first evidence showing that ERAP1 is localized in the ER of trophoblasts and is involved in regulating cell surface HLA-G expression in the presence of LIF [20].

Other interactions of ARTS-1

• The association between endogenous ARTS-1 and NUCB2 in HUVEC was demonstrated by co-immunoprecipitation experiments, which showed the formation of a calcium-dependent NUCB2.ARTS-1 complex that associated with a subset of total cellular TNFR1 [13].
• An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding [21].
• However, the intracellular localization change that accompanied apocrine secretion, which was observed in P-LAP, was not shown in A-LAP [14].
• In an in vivo study, we showed that A-LAP overexpression in endometrial carcinoma cells results in a reduction of VEGF immunoreactivity and the number of blood vessels within tumors [4].
• Consequently, ERAP1 would function to present antigenic peptides to HLA-G in trophoblasts [20].

Analytical, diagnostic and therapeutic context of ARTS-1

• Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 directly binds to a 55-kDa IL-6Ralpha, a size consistent with soluble IL-6Ralpha generated by ectodomain cleavage of the membrane-bound receptor [21].
• Northern blot analysis revealed that A-LAP was expressed in all the tissues tested, some of which expressed at least three forms of mRNA, suggesting that the regulation of the gene expression is complex [15].
• Immunohistochemistry showed strong ERAP1 expression in cultured EVTs [20].
• Flow cytometry with HLA-G antibody to monitor the supply of antigenic peptides presenting to HLA-G in the ER showed that reducing ERAP1 transcripts by RNA interference did not affect cell surface expression of membrane HLA-G1 (mHLA-G1) in JEG-3 cells under basal conditions [20].
• In this study, the role of Lys528 in the enzymatic activity of human A-LAP was examined by site-directed mutagenesis [22].

References