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Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Authors :
Masateru Hiyoshi
Naomi Sakashita
Kazuo Motoyoshi
Hirofumi Akari
Ranya Hassan
Shinya Suzu
Hideki Harada
Seiji Okada
Yuka Yoshidomi
Source :
Blood. 111(1)
Publication Year :
2007

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.

Details

ISSN :
00064971
Volume :
111
Issue :
1
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....d62e132dfd5250627daea913089e701b