Higher-Order Oligomerization Targets Plasma Membrane Proteins and HIV Gag to Exosomes

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Abstract
Exosomes are secreted organelles that have the same topology as the cell and bud outward (outward is defined as away from the cytoplasm) from endosome membranes or endosome-like domains of plasma membrane. Here we describe an exosomal protein-sorting pathway in Jurkat T cells that selects cargo proteins on the basis of both higher-order oligomerization (the oligomerization of oligomers) and plasma membrane association, acts on proteins seemingly without regard to their function, sequence, topology, or mechanism of membrane association, and appears to operate independently of class E vacuolar protein-sorting (VPS) function. We also show that higher-order oligomerization is sufficient to target plasma membrane proteins to HIV virus–like particles, that diverse Gag proteins possess exosomal-sorting information, and that higher-order oligomerization is a primary determinant of HIV Gag budding/exosomal sorting. In addition, we provide evidence that both the HIV late domain and class E VPS function promote HIV budding by unexpectedly complex, seemingly indirect mechanisms. These results support the hypothesis that HIV and other retroviruses are generated by a normal, nonviral pathway of exosome biogenesis. Exosomes are small, secreted organelles with the same topology as the cell and a similar size and composition as retrovirus particles. Based on these similarities, we proposed that retroviruses are, at their most fundamental level, exosomes. Little is known about the mechanisms of exosome biogenesis. We show here that higher-order oligomerization and plasma membrane binding are sufficient to target proteins into both exosomes and HIV virus-like particles. We also find that the HIV protein Gag, which possesses these general exosomal sorting elements, requires only these elements to bud from human cells. Others have proposed that the HIV p6 domain and the host class E vacuolar protein-sorting (VPS) machinery play direct, essential, and mechanistic roles in HIV budding. However, we show here that p6-deficient HIV can bud from cells at normal levels and that both p6-deficient HIV and exosomes can bud independently of class E VPS function. Thus, it appears that exosome biogenesis pathways mediate the budding of HIV from cells, whereas the HIV p6 domain and the class E VPS machinery promote budding indirectly.