Zhang Peixiang, Verity M Anthony, Reue Karen
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Division of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Cell Metab. 2014 Aug 5;20(2):267-79. doi: 10.1016/j.cmet.2014.05.003. Epub 2014 Jun 12.
LPIN1 encodes lipin-1, a phosphatidic acid phosphatase (PAP) enzyme that catalyzes the dephosphorylation of phosphatidic acid to form diacylglycerol. Homozygous LPIN1 gene mutations cause severe rhabdomyolysis, and heterozygous LPIN1 missense mutations may promote statin-induced myopathy. We demonstrate that lipin-1-related myopathy in the mouse is associated with a blockade in autophagic flux and accumulation of aberrant mitochondria. Lipin-1 PAP activity is required for maturation of autolysosomes, through its activation of the protein kinase D (PKD)-Vps34 phosphatidylinositol 3-kinase signaling cascade. Statin treatment also reduces PKD activation and autophagic flux, which are compounded by diminished mammalian target of rapamycin (mTOR) abundance in lipin-1-haploinsufficent and -deficient muscle. Lipin-1 restoration in skeletal muscle prevents myonecrosis and statin toxicity in vivo, and activated PKD rescues autophagic flux in lipin-1-deficient cells. Our findings identify lipin-1 PAP activity as a component of the macroautophagy pathway and define the basis for lipin-1-related myopathies.
LPIN1编码脂联素-1，一种磷脂酸磷酸酶（PAP），可催化磷脂酸去磷酸化形成二酰基甘油。纯合的LPIN1基因突变会导致严重的横纹肌溶解，杂合的LPIN1错义突变可能会促进他汀类药物引起的肌病。我们证明，小鼠中与脂联素-1相关的肌病与自噬通量的阻断和异常线粒体的积累有关。脂联素-1的PAP活性是自噬溶酶体成熟所必需的，它通过激活蛋白激酶D（PKD）-Vps34磷脂酰肌醇3激酶信号级联反应来实现。他汀类药物治疗也会降低PKD的激活和自噬通量，在脂联素-1单倍体不足和缺陷的肌肉中，雷帕霉素哺乳动物靶点（mTOR）丰度的降低会使这种情况更加严重。骨骼肌中脂联素-1的恢复可预防体内的肌坏死和他汀类药物毒性，激活的PKD可挽救脂联素-1缺陷细胞中的自噬通量。我们的研究结果确定脂联素-1的PAP活性是巨自噬途径的一个组成部分，并明确了脂联素-1相关肌病的发病基础。
