A Membrane-sensing Mechanism Links Lipid Metabolism to Protein Degradation at the Nuclear Envelope

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2023 Jun 29

PMID 37382667

Authors

Shoken Lee

Jake W Carrasquillo Rodri Guez

Holly Merta

Shirin Bahmanyar

Affiliations

Soon will be listed here.

Abstract

Lipid composition determines organelle identity; however, whether the lipid composition of the inner nuclear membrane (INM) domain of the ER contributes to its identity is not known. Here, we show that the INM lipid environment of animal cells is under local control by CTDNEP1, the master regulator of the phosphatidic acid phosphatase lipin 1. Loss of CTDNEP1 reduces association of an INM-specific diacylglycerol (DAG) biosensor and results in a decreased percentage of polyunsaturated containing DAG species. Alterations in DAG metabolism impact the levels of the resident INM protein Sun2, which is under local proteasomal regulation. We identify a lipid-binding amphipathic helix (AH) in the nucleoplasmic domain of Sun2 that prefers membrane packing defects. INM dissociation of the Sun2 AH is linked to its proteasomal degradation. We suggest that direct lipid-protein interactions contribute to sculpting the INM proteome and that INM identity is adaptable to lipid metabolism, which has broad implications on disease mechanisms associated with the nuclear envelope.

Citing Articles

Seipin governs phosphatidic acid homeostasis at the inner nuclear membrane.

Romanauska A, Stankunas E, Schuldiner M, Kohler A Nat Commun. 2024; 15(1):10486.

PMID: 39622802 PMC: 11612446. DOI: 10.1038/s41467-024-54811-z.

Amphipathic helices sense the inner nuclear membrane environment through lipid packing defects.

Lee S, Le Roux A, Mors M, Vanni S, Roca-Cusachs P, Bahmanyar S bioRxiv. 2024; .

PMID: 39605395 PMC: 11601446. DOI: 10.1101/2024.11.14.623600.

Mechanisms for assembly of the nucleoplasmic reticulum.

McPhee M, Dellaire G, Ridgway N Cell Mol Life Sci. 2024; 81(1):415.

PMID: 39367888 PMC: 11455740. DOI: 10.1007/s00018-024-05437-3.

The evolutionary origins and ancestral features of septins.

Delic S, Shuman B, Lee S, Bahmanyar S, Momany M, Onishi M Front Cell Dev Biol. 2024; 12:1406966.

PMID: 38994454 PMC: 11238149. DOI: 10.3389/fcell.2024.1406966.

The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after mitosis.

Bragulat-Teixidor H, Ishihara K, Szucs G, Otsuka S EMBO Rep. 2024; 25(7):3137-3159.

PMID: 38877171 PMC: 11239909. DOI: 10.1038/s44319-024-00175-w.

References

Rose A, Zhao C, Turner E, Steyer A, Schlieker C . Arresting a Torsin ATPase reshapes the endoplasmic reticulum. J Biol Chem. 2013; 289(1):552-64. PMC: 3879577. DOI: 10.1074/jbc.M113.515791. View

Behnia R, Munro S . Organelle identity and the signposts for membrane traffic. Nature. 2005; 438(7068):597-604. DOI: 10.1038/nature04397. View

Stone S, Levin M, Farese Jr R . Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2. J Biol Chem. 2006; 281(52):40273-82. DOI: 10.1074/jbc.M607986200. View

Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T . ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016; 44(W1):W344-50. PMC: 4987940. DOI: 10.1093/nar/gkw408. View

Kim Y, Gentry M, Harris T, Wiley S, Lawrence Jr J, Dixon J . A conserved phosphatase cascade that regulates nuclear membrane biogenesis. Proc Natl Acad Sci U S A. 2007; 104(16):6596-601. PMC: 1871831. DOI: 10.1073/pnas.0702099104. View

Bahmanyar S, Schlieker C . Lipid and protein dynamics that shape nuclear envelope identity. Mol Biol Cell. 2020; 31(13):1315-1323. PMC: 7353140. DOI: 10.1091/mbc.E18-10-0636. View

Gautier R, Douguet D, Antonny B, Drin G . HELIQUEST: a web server to screen sequences with specific alpha-helical properties. Bioinformatics. 2008; 24(18):2101-2. DOI: 10.1093/bioinformatics/btn392. View

Lee S, Carrasquillo Rodri Guez J, Merta H, Bahmanyar S . A membrane-sensing mechanism links lipid metabolism to protein degradation at the nuclear envelope. J Cell Biol. 2023; 222(9). PMC: 10309186. DOI: 10.1083/jcb.202304026. View

Surette M, Chilton F . The distribution and metabolism of arachidonate-containing phospholipids in cellular nuclei. Biochem J. 1998; 330 ( Pt 2):915-21. PMC: 1219225. DOI: 10.1042/bj3300915. View

10.

Starr D, Fridolfsson H . Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges. Annu Rev Cell Dev Biol. 2010; 26:421-44. PMC: 4053175. DOI: 10.1146/annurev-cellbio-100109-104037. View

11.

Drin G, Antonny B . Amphipathic helices and membrane curvature. FEBS Lett. 2009; 584(9):1840-7. DOI: 10.1016/j.febslet.2009.10.022. View

12.

Feng S, Sekine S, Pessino V, Li H, Leonetti M, Huang B . Improved split fluorescent proteins for endogenous protein labeling. Nat Commun. 2017; 8(1):370. PMC: 5575300. DOI: 10.1038/s41467-017-00494-8. View

13.

Feng S, Xia C, Zhang P, Shen H . Ab-Initio Membrane Protein Amphipathic Helix Structure Prediction Using Deep Neural Networks. IEEE/ACM Trans Comput Biol Bioinform. 2020; 19(2):795-805. DOI: 10.1109/TCBB.2020.3029274. View

14.

Yesbolatova A, Natsume T, Hayashi K, Kanemaki M . Generation of conditional auxin-inducible degron (AID) cells and tight control of degron-fused proteins using the degradation inhibitor auxinole. Methods. 2019; 164-165:73-80. DOI: 10.1016/j.ymeth.2019.04.010. View

15.

Mall M, Walter T, Gorjanacz M, Davidson I, Ly-Hartig T, Ellenberg J . Mitotic lamin disassembly is triggered by lipid-mediated signaling. J Cell Biol. 2012; 198(6):981-90. PMC: 3444782. DOI: 10.1083/jcb.201205103. View

16.

Majumder S, Willey P, DeNies M, Liu A, Luxton G . A synthetic biology platform for the reconstitution and mechanistic dissection of LINC complex assembly. J Cell Sci. 2018; 132(4). DOI: 10.1242/jcs.219451. View

17.

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

18.

Dechat T, Adam S, Taimen P, Shimi T, Goldman R . Nuclear lamins. Cold Spring Harb Perspect Biol. 2010; 2(11):a000547. PMC: 2964183. DOI: 10.1101/cshperspect.a000547. View

19.

Barbosa A, Lim K, Mari M, Edgar J, Gal L, Sterk P . Compartmentalized Synthesis of Triacylglycerol at the Inner Nuclear Membrane Regulates Nuclear Organization. Dev Cell. 2019; 50(6):755-766.e6. PMC: 6859503. DOI: 10.1016/j.devcel.2019.07.009. View

20.

Rallabandi H, Choi H, Cha H, Kim Y . Research Trends in C-Terminal Domain Nuclear Envelope Phosphatase 1. Life (Basel). 2023; 13(6). PMC: 10301115. DOI: 10.3390/life13061338. View