Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding

The Journal of Clinical Investigation
Xinle CuiStewart J Levine

Abstract

Proteolytic cleavage of TNF receptor 1 (TNFR1) generates soluble receptors that regulate TNF bioactivity. We hypothesized that the mechanism of TNFR1 shedding might involve interactions with regulatory ectoproteins. Using a yeast two-hybrid approach, we identified ARTS-1 (aminopeptidase regulator of TNFR1 shedding) as a type II integral membrane protein that binds to the TNFR1 extracellular domain. In vivo binding of membrane-associated ARTS-1 to TNFR1 was confirmed by coimmunoprecipitation experiments using human pulmonary epithelial and umbilical vein endothelial cells. A direct relationship exists between membrane-associated ARTS-1 protein levels and concordant changes in TNFR1 shedding. Cells overexpressing ARTS-1 demonstrated increased TNFR1 shedding and decreased membrane-associated TNFR1, while cells expressing antisense ARTS-1 mRNA demonstrated decreased membrane-associated ARTS-1, decreased TNFR1 shedding, and increased membrane-associated TNFR1. ARTS-1 neither bound to TNFR2 nor altered its shedding, suggesting specificity for TNFR1. Although a recombinant ARTS-1 protein demonstrated selective aminopeptidase activity toward nonpolar amino acids, multiple lines of negative evidence suggest that ARTS-1 does not possess ...Continue Reading

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Citations

Aug 31, 2011·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Young Ho LeeGwan Gyu Song
Dec 31, 2003·Experimental Cell Research·Ming-Jen HsuShie-Liang Hsieh
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Datasets Mentioned

BETA
NM001065
GM130

Methods Mentioned

BETA
two-hybrid
PMA
PCR
immunoprecipitation
scraping
ELISA

Software Mentioned

BLAST
MEMSAT2
MacVector
TopPred2

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