A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation
A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation
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DOI：
10.1074/jbc.m109.065805
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发表时间：
2010-03-12
影响因子：
4.8
通讯作者：
Garred, Peter
中科院分区：
文献类型：
--
作者：
Skjoedt, Mikkel-Ole;Hummelshoj, Tina;Garred, Peter
人凝集素补体途径涉及由甘露糖结合凝集素（MBL）或三种纤维胶凝蛋白（纤维胶凝蛋白-1、-2和-3）与三种MBL/纤维胶凝蛋白相关丝氨酸蛋白酶（MASP）（MASP-1、-2和-3）和非酶sMAP组成的循环复合物。MASP-1和MASP-3（分别为MASP 1同种型1和2）是MASP 1基因的剪接变体，而MASP-2和sMAP是MASP 2基因的剪接变体。我们已经确定了一种新的45 kDa的血清蛋白，与MBL和纤维胶凝蛋白。这种蛋白质被命名为MBL/纤维胶凝蛋白相关蛋白1（MAP-1，对应于MASP 1同种型3）。产生MAP-1的转录物（MASP1_v3）含有外显子1-8和编码框内终止密码子的新外显子。相应的蛋白质缺乏丝氨酸蛋白酶结构域，但含有MASP-1和MASP-3的大部分共同重链。此外，MAP-1含有17个独特的C-末端氨基酸。通过使用定量PCR和MAP-1特异性免疫组织化学，我们发现MAP-1在心肌和骨骼肌组织以及肝肝细胞中高度表达，其表达谱与MASP-1和MASP-3所观察到的表达谱不同。MAP-1与MBL、纤维胶凝蛋白-2和纤维胶凝蛋白-3从人血清共沉淀，并且重组MAP-1能够通过纤维胶凝蛋白-3和MBL途径抑制补体C4沉积。总之，我们已经确定了一种新的45 kDa的血清蛋白来源于MASP 1基因，这是高度表达的横纹肌组织。发现其与MBL和纤维胶凝蛋白复合，并可作为体内补体系统的有效抑制剂发挥作用。
The human lectin complement pathway involves circulating complexes consisting of mannose-binding lectin (MBL) or three ficolins (ficolin-1, -2, and -3) in association with three MBL/ficolin-associated serine proteases (MASP) (MASP-1, -2, and -3) and a nonenzymatic sMAP. MASP-1 and MASP-3 (MASP1 iso-forms 1 and 2, respectively) are splice variants of the MASP1 gene, whereas MASP-2 and sMAP are splice variants of the MASP2 gene. We have identified a novel serum protein of 45 kDa that is associated with MBL and the ficolins. This protein is named MBL/ficolin-associated protein 1 (MAP-1 corresponding to MASP1 isoform 3). The transcript generating MAP-1 (MASP1_v3) contains exons 1-8 and a novel exon encoding an in-frame stop codon. The corresponding protein lacks the serine protease domains but contains most of the common heavy chain of MASP-1 and MASP-3. Additionally MAP-1 contains 17 unique C-terminal amino acids. By use of quantitative PCR and MAP-1-specific immunohistochemistry, we found that MAP-1 is highly expressed in myocardial and skeletal muscle tissues as well as in liver hepatocytes with a different expression profile than that observed for MASP-1 and MASP-3. MAP-1 co-precipitated from human serum with MBL, ficolin-2, and ficolin-3, and recombinant MAP-1 was able to inhibit complement C4 deposition via both the ficolin-3 and MBL pathway. In conclusion we have identified a novel 45-kDa serum protein derived from the MASP1 gene, which is highly expressed in striated muscle tissues. It is found in complex with MBL and ficolins and may function as a potent inhibitor of the complement system in vivo.