Dys-Regulated Activation of a Src Tyroine Kinase Hck at the Golgi Disturbs N-Glycosylation of a Cytokine Receptor Fms
Dys-Regulated Activation of a Src Tyroine Kinase Hck at the Golgi Disturbs N-Glycosylation of a Cytokine Receptor Fms
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DOI：
10.1002/jcp.21878
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发表时间：
2009-11-01
影响因子：
5.6
通讯作者：
Okada, Seiji
中科院分区：
文献类型：
--
作者：
Hassan, Ranya;Suzu, Shinya;Okada, Seiji
HIV-1 Nef通过与Src激酶Hck结合并激活Src激酶Hck而加速向AIDS的进展，但其潜在的分子基础尚不清楚。我们发现Nef以Hck依赖的方式干扰细胞因子受体Fms的N-糖基化/运输，这可能是恶化不受控制的免疫系统的触发因素。在这里，我们提供了直接的证据，HCK预定位到高尔基体的失调激活导致这种FMS成熟逮捕。一个显着的变化，在HCK诱导的Nef以外的激活是其歪斜的定位到高尔基体，由于主要的高尔基体定位的Nef。对不同Nef等位基因及其突变体的研究表明，较高的Nef-Hck亲和力、较强的Hck激活、Hck严重的高尔基体定位和严重的Fms成熟停滞之间存在明显的相关性。用新发现的Nef-Hck结合阻断剂2c进行的研究更清楚地表明，活性Hck的Golgi倾斜定位确实是Fms成熟停滞的原因。2c阻断了Nef诱导的Hck活性形式（Hck-P2 A）的Golgi倾斜定位和Nef/Hck-P2 A对Fms成熟的阻滞，但对Hck-P2 A激酶活性没有抑制作用。我们的发现建立了一个有趣的联系Nef的发病机制和一个新出现的概念，高尔基体定位Src激酶调节高尔基体功能。J.细胞。221：458-468，2009。(C)2009威利-利斯公司
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. (C) 2009 Wiley-Liss, Inc.