Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes.
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.
Fang
Yi
Y
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Wu
Ning
N
Gan
Xin
X
Yan
Wanhua
W
Morrell
James C
JC
Gould
Stephen J
SJ
D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D015683:Gene Products, gag / Q000378:metabolism*; D006678:HIV / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D015683:Gene Products, gag; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1