Gough P J, Greaves D R, Gordon S
Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
J Lipid Res. 1998 Mar;39(3):531-43.
The class A macrophage scavenger receptors (SR-A) are macrophage-specific trimeric integral membrane glycoproteins that have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. There are two forms of the receptor that have been previously cloned, and both are generated by alternative splicing of a single gene. Here we report the cloning of a third, alternatively spliced isoform of the human SR-A gene (type III hSR-A). The novel isoform is expressed in the human monocytic leukemia cell line THP-1 and also in primary human monocyte derived macrophages. When expressed in CHO-K1 cells, type III hSR-A does not internalize AcLDL despite having the domain shown to mediate this function in type I and II hSR-A. We show that type III protein has altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. Type III protein acts as a dominant negative isoform by reducing modified LDL uptake in CHO cells stably expressing either type I or type II SR-A. The demonstration that a naturally occurring splice variant of SR-A mRNA can act as a dominant negative isoform suggests a novel mechanism for regulation of scavenger receptor activity in macrophages.
A类巨噬细胞清道夫受体（SR-A）是巨噬细胞特异性的三聚体整合膜糖蛋白，与许多巨噬细胞相关的生理和病理过程有关，包括动脉粥样硬化、阿尔茨海默病和宿主防御。先前已克隆出该受体的两种形式，二者均由单个基因的可变剪接产生。在此，我们报告人类SR-A基因（III型hSR-A）的第三种可变剪接异构体的克隆。该新型异构体在人单核细胞白血病细胞系THP-1以及原代人单核细胞衍生的巨噬细胞中均有表达。当在CHO-K1细胞中表达时，尽管III型hSR-A具有在I型和II型hSR-A中显示介导此功能的结构域，但它不会内化乙酰化低密度脂蛋白（AcLDL）。我们表明，III型蛋白的细胞内加工过程发生改变，并被困在内质网中，使其无法进行内吞作用。通过降低稳定表达I型或II型SR-A的CHO细胞中修饰的低密度脂蛋白摄取，III型蛋白可作为显性负性异构体发挥作用。SR-A mRNA的天然剪接变体可作为显性负性异构体这一发现，提示了巨噬细胞中清道夫受体活性调节的一种新机制。
