Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane
Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane
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DOI：
10.1016/j.molcel.2021.02.025
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发表时间：
2021-04-01
期刊：
影响因子：
16
通讯作者：
Suzuki, Jun
中科院分区：
文献类型：
--
作者：
Maruoka, Masahiro;Zhang, Panpan;Suzuki, Jun
死亡细胞中的磷脂紊乱促进磷脂酰丝氨酸暴露，这是红细胞增多症的关键过程。我们以前确定的Xkr家族蛋白Xkr4作为一个磷脂扰乱蛋白，但其激活机制仍然未知。在这里，我们表明，Xkr4被激活在两个步骤：二聚体形成的半胱天冬酶介导的切割和结构变化引起的激活因子。为了确定这些因素，我们开发了一种新的筛选系统，“复兴筛选”，使用CRISPR sgRNA文库。应用这个系统，我们确定核蛋白XRCC4作为Xkr4激活剂的单一候选物。在凋亡刺激下，DNA修复复合物中包含的XRCC4被半胱天冬酶切割，其具有固有无序区域的C末端片段释放到细胞质中。蛋白质相互作用筛选表明，该片段直接与Xkr4二聚体相互作用，激活it.This研究表明，半胱天冬酶介导的切割释放的核蛋白片段的直接调节的脂质动力学质膜。
Phospholipid scrambling in dying cells promotes phosphatidylserine exposure, a critical process for efferocytosis. We previously identified the Xkr family protein Xkr4 as a phospholipid-scrambling protein, but its activation mechanisms remain unknown. Here we show that Xkr4 is activated in two steps: dimer formation by caspase-mediated cleavage and structural change caused by activating factors. To identify the factors, we developed a new screening system, "revival screening," using a CRISPR sgRNA library. Applying this system, we identified the nuclear protein XRCC4 as the single candidate for the Xkr4 activator. Upon apoptotic stimuli, XRCC4, contained in the DNA repair complex, is cleaved by caspases, and its C-terminal fragment with an intrinsically disordered region is released into the cytoplasm. Protein interaction screening showed that the fragment interacts directly with the Xkr4 dimer to activate it. This study demonstrates that caspase-mediated cleavage releases a nuclear protein fragment for direct regulation of lipid dynamics on the plasma membrane.