Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor.
Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colony-stimulating factor (M-CSF), a primary cytokine for macrophages. Here, we show that the inhibitory effect of Nef is due to the Hck-dependent down-regulation of the cell surface expression of M-CSF receptor Fms. In the presence of Hck, Nef induced the accumulation of an immature under-N-glycosylated Fms at the Golgi, thereby down-regulating Fms. The activation of Hck by the direct interaction with Nef was indispensable for the down-regulation. Unexpectedly, the accumulation of the active Hck at the Golgi where Nef prelocalized was likely to be another critical determinant of the function of Nef, because the expression of the constitutive-active forms of Hck alone did not fully down-regulate Fms. These results suggest that Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck.
Hiyoshi
Masateru
M
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo 2-2-1, Kumamoto-city, Kumamoto 860-0811, Japan.
Suzu
Shinya
S
Yoshidomi
Yuka
Y
Hassan
Ranya
R
Harada
Hideki
H
Sakashita
Naomi
N
Akari
Hirofumi
H
Motoyoshi
Kazuo
K
Okada
Seiji
S
D000328:Adult; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology; D006056:Golgi Apparatus / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D007951:Leukemia, Myeloid; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D021381:Protein Transport / Q000276:immunology; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000378:metabolism*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D011956:Receptors, Cell Surface; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D016186:Receptor, Macrophage Colony-Stimulating Factor; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck