daSilva Luis L P, Sougrat Rachid, Burgos Patricia V, Janvier Katy, Mattera Rafael, Bonifacino Juan S
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, MD 20892, USA.
J Virol. 2009 Jul;83(13):6578-90. doi: 10.1128/JVI.00548-09. Epub 2009 Apr 29.
The Nef protein of human immunodeficiency virus type 1 downregulates the CD4 coreceptor from the surface of host cells by accelerating the rate of CD4 endocytosis through a clathrin/AP-2 pathway. Herein, we report that Nef has the additional function of targeting CD4 to the multivesicular body (MVB) pathway for eventual delivery to lysosomes. This targeting involves the endosomal sorting complex required for transport (ESCRT) machinery. Perturbation of this machinery does not prevent removal of CD4 from the cell surface but precludes its lysosomal degradation, indicating that accelerated endocytosis and targeting to the MVB pathway are separate functions of Nef. We also show that both CD4 and Nef are ubiquitinated on lysine residues, but this modification is dispensable for Nef-induced targeting of CD4 to the MVB pathway.
1型人类免疫缺陷病毒的Nef蛋白通过网格蛋白/AP-2途径加速CD4内吞作用的速率，从而下调宿主细胞表面的CD4共受体。在此，我们报告Nef具有将CD4靶向多囊泡体（MVB）途径以便最终转运至溶酶体的额外功能。这种靶向作用涉及运输所需的内体分选复合物（ESCRT）机制。该机制的扰动并不妨碍CD4从细胞表面的移除，但会阻止其溶酶体降解，这表明加速内吞作用和靶向MVB途径是Nef的不同功能。我们还表明，CD4和Nef在赖氨酸残基上都被泛素化，但这种修饰对于Nef诱导的CD4靶向MVB途径来说并非必需。
