PDF(Pubmed)
Abstract：
Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in CHKB, encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in Chkb -/- mice there is a failure of the α7β1 integrin complex that is specific to affected muscle. We observed that in Chkb -/- hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P2 binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P2 reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of CHKB.
摘要：
磷脂酰胆碱（PC）是大多数真核细胞中的主要膜磷脂。CHKB中功能变体的双等位基因缺失，编码合成PC的第一步，是人类和小鼠的rostrocautal肌营养不良的原因。肌膜完整性的丧失是肌营养不良的标志；然而，在缺乏胆碱激酶功能的情况下，这种情况是如何发生的尚不清楚。我们确定在Chkb-/-小鼠中存在对受影响的肌肉特异性的α7β1整联蛋白复合物的失败。我们观察到在Chkb-/-后肢肌肉中，PI（4,5）P2结合整合素复合物蛋白的肌膜缔合/丰度降低，和α-肌动蛋白，肌动蛋白与肌膜的结合减少。在细胞中，胆碱激酶活性的药理学抑制导致荧光PI（4,5）P2报告分子从细胞表面膜的离散质膜簇内化到细胞质，这与通过CHKB的过表达挽救的质膜粘着斑上的黏珠蛋白定位减少相对应.
