Original Research Article
HIV-1 Nef perturbs the function, structure, and signaling of the Golgi through the Src Kinase Hck
Article first published online: 22 DEC 2011
Copyright © 2011 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 227, Issue 3, pages 1090–1097, March 2012
How to Cite
Hiyoshi, M., Takahashi-Makise, N., Yoshidomi, Y., Chutiwitoonchai, N., Chihara, T., Okada, M., Nakamura, N., Okada, S. and Suzu, S. (2012), HIV-1 Nef perturbs the function, structure, and signaling of the Golgi through the Src Kinase Hck. J. Cell. Physiol., 227: 1090–1097. doi: 10.1002/jcp.22825
- Issue published online: 22 DEC 2011
- Article first published online: 22 DEC 2011
- Accepted manuscript online: 12 MAY 2011 07:44AM EST
- Manuscript Accepted: 21 APR 2011
- Manuscript Received: 19 NOV 2010
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
The interaction between HIV-1 Nef and the Src kinase Hck in macrophages has been shown to accelerate the progression to AIDS. We previously showed that Nef disturbed the N-glycosylation/trafficking of Fms, a cytokine receptor essential for maintaining macrophages in an anti-inflammatory state, in an Hck-dependent manner. Here, we show the underlying molecular mechanism of this effect. Using various Hck isoforms and their mutants and Golgi-targeting Hck mutants, we confirmed that Hck activation at the Golgi causes the Nef-induced Fms N-glycosylation defect. Importantly, we found that both the co-expression of Nef and Hck and the expression of a Golgi-targeted active Hck mutant caused alterations in the distribution of GM130, a Golgi protein that was shown to be required for efficient protein glycosylation. Moreover, the activation of Hck at the Golgi caused strong serine phosphorylation of the GM130-interacting Golgi structural protein GRASP65, which is known to induce Golgi cisternal unstacking. Using pharmacological inhibitors, we also found that the activation of Hck at the Golgi followed by the activation of the MAP kinase ERK-GRASP65 cascade is involved in the Fms N-glycosylation defect. These results suggest that Nef perturbs the structure and signaling of the Golgi by activating Hck at the Golgi, and thereby, induces the N-glycosylation/trafficking defect of Fms, which is in line with the idea that Src family kinases are crucial Golgi regulators. J. Cell. Physiol. 227: 1090–1097, 2012. © 2011 Wiley Periodicals, Inc.