Dys-regulated activation of a Src tyroine kinase Hck at the Golgi disturbs N-glycosylation of a cytokine receptor Fms |
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| Authors: | Ranya Hassan Shinya Suzu Masateru Hiyoshi Naoko Takahashi-Makise Takamasa Ueno Tsutomu Agatsuma Hirofumi Akari Jun Komano Yutaka Takebe Kazuo Motoyoshi Seiji Okada |
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| Institution: | 1. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Kumamoto, Japan;2. Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Kumamoto, Japan;3. Tokyo Research Laboratories, Kyowa Hakko Co., Ltd, Machida, Tokyo, Japan;4. Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan;5. Laboratory of Virology and Pathogenesis, AIDS Research Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan;6. Laboratory of Molecular Biology and Epidemiology, AIDS Research Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan;7. Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan |
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| Abstract: | HIV-1 Nef accelerates the progression to AIDS by binding with and activating a Src kinase Hck, but underlying molecular basis is not understood. We revealed that Nef disturbed N-glycosylation/trafficking of a cytokine receptor Fms in an Hck-dependent manner, a possible trigger to worsen uncontrolled immune system. Here, we provide direct evidence that dys-regulated activation of Hck pre-localized to the Golgi apparatus causes this Fms maturation arrest. A striking change in Hck induced by Nef other than activation was its skewed localization to the Golgi due to predominant Golgi-localization of Nef. Studies with different Nef alleles and their mutants showed a clear correlation among higher Nef-Hck affinity, stronger Hck activation, severe Golgi-localization of Hck and severe Fms maturation arrest. Studies with a newly discovered Nef-Hck binding blocker 2c more clearly showed that skewed Golgi-localization of active Hck was indeed the cause of Fms maturation arrest. 2c blocked Nef-induced skewed Golgi-localization of an active form of Hck (Hck-P2A) and Fms maturation arrest by Nef/Hck-P2A, but showed no inhibition on Hck-P2A kinase activity. Our finding establishes an intriguing link between the pathogenesis of Nef and a newly emerging concept that the Golgi-localized Src kinases regulate the Golgi function. J. Cell. Physiol. 221: 458–468, 2009. © 2009 Wiley-Liss, Inc. |
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