Abstract
Lipin-1 catalyzes the formation of diacylglycerol from phosphatidic acid. 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 nem1Δspo7Δ 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. The expression 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 CTDNEP1 and NEP1-R1 are co-expressed. Therefore, NEP1-R1 is functionally conserved from yeast to humans and functions in the lipin activation pathway.
Highlights
TMEM188 Is a Candidate for the Human Spo7p Ortholog— In yeast, Nem1p associates with Spo7p in a phosphatase complex to dephosphorylate the yeast lipin ortholog, Pah1p [21]
The first hint of an Spo7p mammalian homolog was given by the PROCAIN program [47], which found TMEM188 (GI 31542781) as the first hit encoded by the human genome
We have found the metazoan ortholog for the lipin-1/Pah1p coactivator Spo7p, TMEM188, here renamed nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1)
Summary
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. Pah1p is inactivated by phosphorylation by Cdc28p and likely by other kinases [21, 27] and activated by dephosphorylation by a nuclear envelope membrane complex consisting of Nem1p and Spo7p, with Nem1p being the catalytic subunit [21]. In the absence of Pah1p or its activators in yeast, there is a severe decrease in TAG levels and lipid droplets and an expansion of the nuclear envelope, consistent with a decrease in DAG and an increase in phospholipid synthesis caused by the sequestration of the transcriptional regulator Opi1p by PA in the ER membrane [11, 16, 28, 29]. In the presence of CTDNEP1 and NEP1-R1 together, there is an accumulation of lipin in the nucleus
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