Greenberg M E, Iafrate A J, Skowronski J
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
EMBO J. 1998 May 15;17(10):2777-89. doi: 10.1093/emboj/17.10.2777.
Nef, a regulatory protein of human and simian immunodeficiency viruses, downregulates cell surface expression of both class I MHC and CD4 molecules in T cells by accelerating their endocytosis. Fibroblasts were used to study alterations in the traffic of class I MHC complexes induced by Nef. We found that Nef downregulates class I MHC complexes by a novel mechanism involving the accumulation of endocytosed class I MHC in the trans-Golgi, where it colocalizes with the adaptor protein-1 complex (AP-1). This effect of Nef on class I MHC traffic requires the SH3 domain-binding surface and a cluster of acidic amino acid residues in Nef, both of which are also required for Nef to downregulate class I MHC surface expression and to alter signal transduction in T cells. Downregulation of class I MHC complexes from the surface of T cells also requires a tyrosine residue in the cytoplasmic domain of the class I MHC heavy chain molecule. The requirement of the same surfaces of the Nef molecule for downregulation of surface class I MHC complexes in T cells and for their accumulation in the trans-Golgi of fibroblasts indicates that the two effects of Nef involve similar interactions with the host cell machinery and involve a molecular mechanism regulating class I MHC traffic that is common for both of these cell types. Interestingly, the downregulation of class I MHC does not require the ability of Nef to colocalize with the adaptor protein-2 complex (AP-2). We showed previously that the ability of Nef to colocalize with AP-2 correlates with the ability of Nef to downregulate CD4 expression. Our observations indicate that Nef downregulates class I MHC and CD4 surface expression via different interactions with the protein sorting machinery, and link the sorting and signal transduction machineries in the regulation of class I MHC surface expression by Nef.
Nef是人类和猿猴免疫缺陷病毒的一种调节蛋白，它通过加速I类主要组织相容性复合体（MHC）和CD4分子的内吞作用来下调T细胞表面这两种分子的表达。成纤维细胞被用于研究Nef诱导的I类MHC复合体运输变化。我们发现，Nef通过一种新机制下调I类MHC复合体，该机制涉及内吞的I类MHC在反式高尔基体中的积累，在那里它与衔接蛋白-1复合体（AP-1）共定位。Nef对I类MHC运输的这种作用需要Nef中的SH3结构域结合表面和一簇酸性氨基酸残基，这两者也是Nef下调I类MHC表面表达和改变T细胞信号转导所必需的。从T细胞表面下调I类MHC复合体还需要I类MHC重链分子胞质结构域中的一个酪氨酸残基。Nef分子的相同表面对于下调T细胞表面I类MHC复合体以及使其在成纤维细胞的反式高尔基体中积累的需求表明，Nef的这两种作用涉及与宿主细胞机制的相似相互作用，并且涉及一种调节这两种细胞类型中I类MHC运输的分子机制。有趣的是，I类MHC的下调并不需要Nef与衔接蛋白-2复合体（AP-2）共定位的能力。我们之前表明，Nef与AP-2共定位的能力与Nef下调CD4表达的能力相关。我们的观察结果表明，Nef通过与蛋白质分选机制的不同相互作用下调I类MHC和CD4的表面表达，并在Nef调节I类MHC表面表达的过程中连接了分选和信号转导机制。
