A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia.
A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia.
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DOI：
10.1083/jcb.201503067
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发表时间：
2015-10-26
期刊：
影响因子：
--
通讯作者：
Hong Y
中科院分区：
文献类型：
--
作者：
Dong W;Zhang X;Liu W;Chen YJ;Huang J;Austin E;Celotto AM;Jiang WZ;Palladino MJ;Jiang Y;Hammond GR;Hong Y
LGL是一种关键的极性和肿瘤抑制蛋白，它的质膜靶向性是通过LGL中的一个多碱基序与质膜上的磷脂之间的静电相互作用来调节的，这一机制受到缺氧和aPKC磷酸化的调节。致死巨型幼虫(LGL)在调节果蝇、黑腹果蝇和脊椎动物的细胞极性和肿瘤发生中发挥着重要而保守的功能。众所周知，质膜(PM)或细胞皮质定位对LGL在体内的功能至关重要，但其膜靶向机制尚不清楚。在这里，我们发现，低氧通过一种翻译后机制急性和可逆地抑制LGL PM靶向，该机制独立于已有的非典型蛋白激酶C(APKC)或极光激酶介导的磷酸化。相反，我们确定了一个进化保守的多碱(PB)结构域，它通过与膜磷脂酰肌醇磷酸盐的静电结合来靶向LGL到PM。这种PB结构域介导的PM靶向性被低氧抑制，低氧通过耗尽三磷酸腺苷降低PM上的肌醇磷脂水平。此外，LGLPB结构域包含所有已发现的aPKC和Aurora激酶的磷酸化位点，提供了一种分子机制，通过磷酸化中和PB结构域上的正电荷来抑制LGLPM靶向。
The plasma membrane targeting of Lgl, a key polarity and tumor suppressor protein, is mediated by electrostatic interactions between a polybasic motif in Lgl and phospholipids on the plasma membrane, and this mechanism is regulated by hypoxia and aPKC-phosphorylation. Lethal giant larvae (Lgl) plays essential and conserved functions in regulating both cell polarity and tumorigenesis in Drosophila melanogaster and vertebrates. It is well recognized that plasma membrane (PM) or cell cortex localization is crucial for Lgl function in vivo, but its membrane-targeting mechanisms remain poorly understood. Here, we discovered that hypoxia acutely and reversibly inhibits Lgl PM targeting through a posttranslational mechanism that is independent of the well-characterized atypical protein kinase C (aPKC) or Aurora kinase–mediated phosphorylations. Instead, we identified an evolutionarily conserved polybasic (PB) domain that targets Lgl to the PM via electrostatic binding to membrane phosphatidylinositol phosphates. Such PB domain–mediated PM targeting is inhibited by hypoxia, which reduces inositol phospholipid levels on the PM through adenosine triphosphate depletion. Moreover, Lgl PB domain contains all the identified phosphorylation sites of aPKC and Aurora kinases, providing a molecular mechanism by which phosphorylations neutralize the positive charges on the PB domain to inhibit Lgl PM targeting.