Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor.
Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor.
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DOI：
10.1371/journal.pone.0118835
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Maru Y
中科院分区：
文献类型：
--
作者：
Tomita T;Ieguchi K;Sawamura T;Maru Y
血清淀粉样蛋白A3（SAA 3）具有不同于其他血清淀粉样蛋白A同种型SAA 1、SAA 2和SAA 4的特征。高密度脂蛋白含有后三种亚型，但不含SAA 3。已知小鼠SAA 3（mSAA 3）的表达在炎症反应中在肝外上调，并且充当toll样受体4/MD-2复合物的内源性配体。我们先前报道mSAA 3通过吸引循环肿瘤细胞和增强肺中的高通透性在促进肿瘤转移中起重要作用。另一方面，人SAA 3（hSAA 3）长期以来被认为是假基因，这与其他同种型的丰富表达水平形成对比。虽然hSAA 3的核苷酸序列与其他SAA的核苷酸序列非常相似，但外显子2中的单个寡核苷酸插入引起移码以产生独特的氨基酸序列。在本研究中，我们确定，hSAA 3转录的hSAA 2-SAA 3融合转录的几种人类细胞系。在融合转录本中，hSAA 2外显子3与hSAA 3外显子1或hSAA 3外显子2相连，位于基因组中hSAA 2外显子3下游约130 kb处，这表明它是通过选择性剪接产生的。此外，我们成功地检测和分离hSAA 3蛋白的第一次通过免疫沉淀酶联免疫分析系统使用单克隆抗体和多克隆抗体，识别的hSAA 3独特的氨基酸序列。我们还证明，hSAA 3结合氧化低密度脂蛋白受体（oxLDL受体，LOX-1），并提高磷酸化的ERK，细胞内的MAP激酶信号蛋白。
Serum amyloid A3 (SAA3) possesses characteristics distinct from the other serum amyloid A isoforms, SAA1, SAA2, and SAA4. High density lipoprotein contains the latter three isoforms, but not SAA3. The expression of mouse SAA3 (mSAA3) is known to be up-regulated extrahepatically in inflammatory responses, and acts as an endogenous ligand for the toll-like receptor 4/MD-2 complex. We previously reported that mSAA3 plays an important role in facilitating tumor metastasis by attracting circulating tumor cells and enhancing hyperpermeability in the lungs. On the other hand, human SAA3 (hSAA3) has long been regarded as a pseudogene, which is in contrast to the abundant expression levels of the other isoforms. Although the nucleotide sequence of hSAA3 is very similar to that of the other SAAs, a single oligonucleotide insertion in exon 2 causes a frame-shift to generate a unique amino acid sequence. In the present study, we identified that hSAA3 was transcribed in the hSAA2-SAA3 fusion transcripts of several human cell lines. In the fusion transcript, hSAA2 exon 3 was connected to hSAA3 exon 1 or hSAA3 exon 2, located approximately 130kb downstream from hSAA2 exon 3 in the genome, which suggested that it is produced by alternative splicing. Furthermore, we succeeded in detecting and isolating hSAA3 protein for the first time by an immunoprecipitation-enzyme linked immune assay system using monoclonal and polyclonal antibodies that recognize the hSAA3 unique amino acid sequence. We also demonstrated that hSAA3 bound oxidized low density lipoprotein receptor (oxLDL receptor, LOX-1) and elevated the phosphorylation of ERK, the intracellular MAP-kinase signaling protein.
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