A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function.
A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function.
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DOI：
10.1038/icb.2016.20
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发表时间：
2016-08
影响因子：
4
通讯作者：
Bowdish DM
中科院分区：
文献类型：
--
作者：
Novakowski KE;Huynh A;Han S;Dorrington MG;Yin C;Tu Z;Pelka P;Whyte P;Guarné A;Sakamoto K;Bowdish DM
胶原结构巨噬细胞受体（MARCO）是一种a类清道夫受体（cA-SR），可识别和吞噬多种病原体。大多数含有c端富含半胱氨酸（SRCR）结构域的ca - sr使用近端胶原结构域结合配体。相比之下，MARCO的SRCR结构域在吞噬、粘附和促炎信号传导中的作用尚不清楚。缺乏SRCR结构域的天然转录物变体MARCOII的发现，为研究MARCO的SRCR结构域的作用提供了机会。我们测试了SRCR结构域是否为配体结合、促进下游信号传导和增强细胞粘附所必需。与表达全长MARCO的细胞不同，在表达marcoii的细胞中，配体结合被取消。此外，MARCO和MARCOII的共表达损害了吞噬功能，表明MARCOII是显性阴性变体。与MARCO不同的是，MARCOII的表达并没有增强toll样受体2 （TLR2）介导的促炎信号在细菌刺激下的作用。表达marco的细胞黏附性更强，表现出树突样表型，而表达marcoii的细胞黏附性较差，没有表现出形态变化。这些数据表明，MARCO的SRCR结构域是调节配体结合、增强下游促炎信号和MARCO介导的细胞粘附的关键结构域。
Macrophage receptor with collagenous structure (MARCO) is a Class A Scavenger Receptor (cA-SR) that recognizes and phagocytoses of a wide variety of pathogens. Most cA-SRs that contain a C-terminal Scavenger Receptor Cysteine Rich (SRCR) domain use the proximal collagenous domain to bind ligands. In contrast, for the role of the SRCR domain of MARCO in phagocytosis, adhesion and pro-inflammatory signalling is less clear. The discovery of a naturally-occurring transcript variant lacking the SRCR domain, MARCOII, provided the opportunity to study the role of the SRCR domain of MARCO. We tested whether the SRCR domain is required for ligand binding, promoting downstream signalling, and enhancing cellular adhesion. Unlike cells expressing full-length MARCO, ligand binding was abolished in MARCOII-expressing cells. Furthermore, co-expression of MARCO and MARCOII impaired phagocytic function, indicating that MARCOII acts as a dominant negative variant. Unlike MARCO, expression of MARCOII did not enhance Toll-Like Receptor 2 (TLR2)-mediated pro-inflammatory signalling in response to bacterial stimulation. MARCO-expressing cells were more adherent and exhibited a dendritic-like phenotype, while MARCOII-expressing cells were less adherent and did not exhibit changes in morphology. These data suggest the SRCR domain of MARCO is the key domain in modulating ligand binding, enhancing downstream pro-inflammatory signalling, and MARCO-mediated cellular adhesion.