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Blood, 1 January 2008, Vol. 111, No. 1, pp. 243-250. Prepublished online as a Blood First Edition Paper on September 24, 2007; DOI 10.1182/blood-2007-04-086017. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-086017v1 111/1/243    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hiyoshi, M. Articles by Okada, S. Search for Related Content PubMed PubMed Citation Articles by Hiyoshi, M. Articles by Okada, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 17, 2007 Accepted September 18, 2007 Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor Masateru Hiyoshi, Shinya Suzu, Yuka Yoshidomi, Ranya Hassan, Hideki Harada, Naomi Sakashita, Hirofumi Akari, Kazuo Motoyoshi, and Seiji Okada* Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan Department of Cell Pathology, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan Third Department of Internal Medicine, National Defense Medical College, Saitama, Japan * Corresponding author; email: okadas{at}gpo.kumamoto-u.ac.jp. Nef is a multi-functional 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 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 pre-localized 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. B. Sehgal, S. Mukhopadhyay, K. Patel, F. Xu, S. Almodovar, R. M. Tuder, and S. C. Flores Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L729 - L737. [Abstract] [Full Text] [PDF] K. M. Atkins, L. Thomas, R. T. Youker, M. J. Harriff, F. Pissani, H. You, and G. Thomas HIV-1 Nef Binds PACS-2 to Assemble a Multikinase Cascade That Triggers Major Histocompatibility Complex Class I (MHC-I) Down-regulation: ANALYSIS USING SHORT INTERFERING RNA AND KNOCK-OUT MICE J. Biol. Chem., April 25, 2008; 283(17): 11772 - 11784. [Abstract] [Full Text] [PDF]

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