Characterization of the Role of NUCB2 in Asthma Pathogenesis

我们实验室先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）从细胞释放到细胞外空间中的作用，其机制可能涉及调节囊泡运输。我们利用酵母双杂交筛选鉴定出ARTS-1（肿瘤坏死因子脱落的氨基肽酶调节因子）是tnfr1结合蛋白，NUCB2是ARTS-1结合蛋白。NUCB2 （nucleobindin 2）是一种EF-hand，螺旋-环-螺旋蛋白结合ARTS-1，从而参与介导TNFR1释放到细胞外空间的机制（J Biol Chem 2006; 28: 6860 6873）。NUCB2和ARTS-1在细胞质囊泡中与TNFR1共定位，并通过TNFR1胞外结构域的蛋白水解裂解和TNFR1外泌体样囊泡的释放两种机制调节TNFR1从细胞向胞外空间的释放（J clinical journal; 2002; 11: 515-526）。本项目利用NUCB2基因敲除小鼠，研究NUCB2基因在实验性小鼠屋尘螨诱发哮喘发病机制中的作用。

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 NUCB2 in the pathogenesis of experimental murine house dust mite-induced asthma.