title: Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor.
abstract: 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.
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo 2-2-1, Kumamoto-city, Kumamoto 860-0811, Japan.
authors: Masateru
authors: M
authors: Hiyoshi
authors: Shinya
authors: S
authors: Suzu
authors: Yuka
authors: Y
authors: Yoshidomi
authors: Ranya
authors: R
authors: Hassan
authors: Hideki
authors: H
authors: Harada
authors: Naomi
authors: N
authors: Sakashita
authors: Hirofumi
authors: H
authors: Akari
authors: Kazuo
authors: K
authors: Motoyoshi
authors: Seiji
authors: S
authors: Okada
mesh_terms: 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*
chemical_list: 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