title: Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum.
abstract: Cells of Saccharomyces cerevisiae lacking Apq12, a nuclear envelope (NE)-endoplasmic reticulum (ER) integral membrane protein, are defective in assembly of nuclear pore complexes (NPCs), possibly because of defects in regulating membrane fluidity. We identified BRR6, which encodes an essential integral membrane protein of the NE-ER, as a dosage suppressor of apq12 Delta. Cells carrying the temperature-sensitive brr6-1 allele have been shown to have defects in nucleoporin localization, mRNA metabolism and nuclear transport. Electron microscopy revealed that brr6-1 cells have gross NE abnormalities and proliferation of the ER. brr6-1 cells were hypersensitive to compounds that affect membrane biophysical properties and to inhibitors of lipid biosynthetic pathways, and displayed strong genetic interactions with genes encoding non-essential lipid biosynthetic enzymes. Strikingly, brr6-1 cells accumulated, in or near the NE, elevated levels of the two classes of neutral lipids, steryl esters and triacylglycerols, and over-accumulated sterols when they were provided exogenously. Although neutral lipid synthesis is dispensable in wild-type cells, viability of brr6-1 cells was fully dependent on neutral lipid production. These data indicate that Brr6 has an essential function in regulating lipid homeostasis in the NE-ER, thereby impacting NPC formation and nucleocytoplasmic transport.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hodge
authors.forename: Vineet
authors.initials: V
authors.lastname: Choudhary
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wolyniak
authors.forename: John J
authors.initials: JJ
authors.lastname: Scarcelli
authors.forename: Roger
authors.initials: R
authors.lastname: Schneiter
authors.forename: Charles N
authors.initials: CN
authors.lastname: Cole
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D004721:Endoplasmic Reticulum; D050356:Lipid Metabolism / Q000235:genetics; D008560:Membrane Fluidity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism*; D022022:Nuclear Pore / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D013696:Temperature; D014280:Triglycerides / Q000378:metabolism
chemical_list: C524955:Apq12 protein, S cerevisiae; C435210:Brr6 protein, S cerevisiae; D008565:Membrane Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; D014280:Triglycerides