Characterization of the Role of NUCB2 in Asthma Pathogenesis

NUCB2 在哮喘发病机制中作用的表征

• 批准号: 8344859
• 负责人: Stewart Levine
• 金额: $ 28.4万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344859
• 关键词: Aminopeptidase; Asthma; Binding Proteins; Cells; Cytoplasmic Vesicles; EF Hand Motifs; Extracellular Space; Goals; Helix-Turn-Helix Motifs; Knockout Mice; Mediating; Mus; Pathogenesis; Protein Binding; Pyroglyphidae; Regulation; Role; TNFRSF1A gene; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Vesicle; Yeasts; extracellular; knockout gene; nucleobindin; trafficking; yeast two hybrid system

Prior studies from our lab have identified a role for NUCB2 in regulating the release of the type I, 55-kDa tumor necrosis factor receptor (TNFR1) from cells to the extracellular space, via a mechanism that may involve the regulation of vesicular trafficking. We utilized yeast two-hybrid screens to identify ARTS-1 (aminopeptidase regulator of tumor necrosis factor shedding) as a TNFR1-binding protein and NUCB2 as an ARTS-1-binding protein. NUCB2 (nucleobindin 2) is an EF-hand, helix-loop-helix protein that binds ARTS-1 and thereby participates in the mechanism mediating the release of TNFR1 to the extracellular space (J Biol Chem 2006; 281: 6860 6873). NUCB2 and ARTS-1 co-localize with TNFR1 in cytoplasmic vesicles and regulate the release of TNFR1 from cells to the extracellular space by two mechanisms, the proteolytic cleavage of TNFR1 ectodomains and the release of TNFR1 exosome-like vesicles (J Clin Invest 2002; 110: 515-526). This project is utilizing NUCB2 knockout mice to investigate the role of this ARTS-1-binding protein in the pathogenesis of experimental murine house dust mite-induced asthma.

我们实验室以前的研究已经确定了NUCB2在调节I型55-kDa肿瘤坏死因子受体(TNFR1)从细胞到细胞外间隙的释放中的作用，其机制可能涉及囊泡运输的调节。我们利用酵母双杂交筛选法鉴定了ARTS-1(肿瘤坏死因子脱落的氨基肽酶调节因子)为TNFR1结合蛋白，NUCB2为ARTS-1结合蛋白。NUCB2(核结合蛋白2)是一种EF-手，螺旋-环-螺旋蛋白，它与ARTS-1结合，从而参与介导TNFR1释放到细胞外空间的机制(J Biol Chem 2006；281：6860 6873)。NUCB2和ARTS-1与TNFR1共同定位于细胞质小泡中，通过两种机制调节TNFR1从细胞到细胞外间隙的释放，即TNFR1胞外区的蛋白水解性切割和TNFR1外体样囊泡的释放(J Clin Invest 2002；110：515-526)。本项目利用NUCB2基因敲除小鼠来研究这种ARTS-1结合蛋白在实验性小鼠屋尘螨诱导的哮喘发病机制中的作用。