title: Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway.
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.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Sungwon
authors.initials: S
authors.lastname: Han
authors.forename: Shirin
authors.initials: S
authors.lastname: Bahmanyar
authors.forename: Peixiang
authors.initials: P
authors.lastname: Zhang
authors.forename: Nick
authors.initials: N
authors.lastname: Grishin
authors.forename: Karen
authors.initials: K
authors.lastname: Oegema
authors.forename: Roseann
authors.initials: R
authors.lastname: Crooke
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.forename: Joel M
authors.initials: JM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009685:Nuclear Envelope / Q000201:enzymology / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C116365:SPO7 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D054645:Protein Phosphatase 1; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase