Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum

Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
Journal of Cell Science (Impact Factor: 5.43). 01/2010; 123(Pt 1):141-51. DOI: 10.1242/jcs.055046
Source: PubMed


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.

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Available from: Michael J Wolyniak, May 07, 2015
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    • "However, we observed a strong phenotype for a mutant in APQ12. The activity of Apq12p is not clear but its deletion leads to a strong accumulation of TAG [67], which could also drain the pools of DAG and PA. "
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    • "Ndc1 has roles at both SPBs and NPCs (Winey et al. 1993; Chial et al. 1998; Lau et al. 2004). Two other NE membrane proteins, Brr6 and Apq12, have also been linked to both NPC biogenesis and SPB insertion (Scarcelli et al. 2007; Hodge et al. 2010; Schneiter and Cole 2010; Tamm et al. 2011). To test for specificity, BRR6 and APQ12 overexpression was analyzed . "
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    • "Similarly, the NE/ER proteins Apq12p and Brr6p are genetically linked to each other and are necessary for normal NPC assembly and distribution. This work indicates that both proteins are involved in maintaining lipid homoeostasis in the ER, which is necessary for proper NPC insertion and distribution in the NE (Scarcelli et al. 2007; Hodge et al. 2010). Another candidate NPC assembly factor is Pom33p, isolated in a genetic screen for genes that are essential in cells lacking Nup133p (Chadrin et al. 2010). "
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