Ectodomain shedding of TNF-α is enhanced by nardilysin via activation of ADAM proteases

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• 作者：Yoshinori Hiraoka ; Kazuhiro Yoshida ; Mikiko Ohno ; Tatsuhiko Matsuoka ; Toru Kita ; Eiichiro Nishi
• 关键词：Nardilysin ; Ectodomain shedding ; Tumor necrosis factor-<img src="http ; //www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> (TNF-<img src="http ; //www.sciencedirect.com/scidirimg/en
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2008
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：23 May 2008
• 卷：370
• 期：1
• 页码：154-158
• 文件大小：469 K

摘要

Tumor necrosis factor-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> (TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">) is released from cells by proteolytic cleavage of a membrane-anchored precursor. The TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">. At present, however, it is poorly understood how its catalytic activity is regulated. Here, we show that nardilysin (N-arginine dibasic convertase; NRDc) enhanced TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> shedding. In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> shedding. A peptide cleavage assay in vitro showed that recombinant NRDc enhances the cleavage of TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> induced by TACE. Notably, co-incubation of NRDc completely reversed the inhibitory effect of a physiological concentration of salt on TACE’s activity in vitro. Overexpression of NRDc in TACE-deficient fibroblasts resulted in an increase in the amount of TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> released. Co-expression of NRDc with ADAM10 promoted the release compared with the sole expression of ADAM10. These results suggested that NRDc enhances TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> shedding through activation of not only TACE but ADAM10. Our results indicate the involvement of NRDc in ectodomain shedding of TNF-<img src="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">, which may be a novel target for anti-inflammatory therapies.