Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway
Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway
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DOI：
10.1074/jbc.m111.324350
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发表时间：
2012-01-27
影响因子：
4.8
通讯作者：
Goodman, Joel M.
中科院分区：
文献类型：
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作者：
Han, Sungwon;Bahmanyar, Shirin;Goodman, Joel M.
脂素-1催化磷脂酸生成二酰基甘油。脂素-1突变导致小鼠脂肪营养不良和人类急性肌病。它被严重磷酸化，酵母同源物Pah1p在Nem1p-Spo7p膜复合物去磷酸化后变得与膜相关并具有活性。Nem1p的哺乳动物同源物是c端结构域核包膜磷酸酶1 （CTDNEP1，以前称为“dullard”），但其类似spo7p的伙伴是未知的，其存在的必要性也存在争议。在这里，我们确定了Spo7p的后生同源物，TMEM188，更名为核膜磷酸酶1调控亚基1 （NEP1-R1）。CTDNEP1和NEP1-R1共同补充nem1 δ spo7 δ菌株，阻断内质网增殖，恢复甘油三酯水平和脂滴数量。这两种人类同源基因在细胞中处于一个复合体中，当NEP1-R1存在时，CTDNEP1的数量增加。在秀丽隐杆线虫胚胎中，线虫CTDNEP1和NEP1-R1以及脂素-1的表达是合子形成后核膜正常破裂所必需的。NEP1-R1和CTDNEP1在人和小鼠组织中的表达模式与lipin-1非常相似。只有在NEP1-R1存在的情况下，CTDNEP1才能使人细胞中的脂素-1a、-1b和-2去磷酸化。当CTD-NEP1和NEP1-R1共表达时，脂素-1b的核分数增加。因此，从酵母到人类，NEP1-R1在功能上是保守的，并且在脂素激活途径中起作用。
Lipin-1 catalyzes the formation of diacylglycerol from phosphatidicacid. Lipin-1 mutations cause lipodystrophy in mice and acute myopathy in humans. It is heavily phosphorylated, and the yeast ortholog Pah1p becomes membrane-associated and active upon dephosphorylation by the Nem1p-Spo7p membrane complex. A mammalian ortholog of Nem1p is the C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly "dullard"), but its Spo7p-like partner is unknown, and the need for its existence is debated. Here, we identify the metazoan ortholog of Spo7p, TMEM188, renamed nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1). CTDNEP1 and NEP1-R1 together complement a nem1 Delta spo7 Delta strain to block endoplasmic reticulum proliferation and restore triacylglycerol levels and lipid droplet number. The two human orthologs are in a complex in cells, and the amount of CTDNEP1 is increased in the presence of NEP1-R1. In the Caenorhabditis elegans embryo, expression of nematode CTDNEP1 and NEP1-R1, as well as lipin-1, is required for normal nuclear membrane breakdown after zygote formation. Theexpression pattern of NEP1-R1 and CTDNEP1 in human and mouse tissues closely mirrors that of lipin-1. CTDNEP1 can dephosphorylate lipins-1a, -1b, and -2 in human cells only in the presence of NEP1-R1. The nuclear fraction of lipin-1b is increased when CTD-NEP1 and NEP1-R1 are co-expressed. Therefore, NEP1-R1 is functionally conserved from yeast to humans and functions in the lipin activation pathway.