[en] To date, precise roles of EMD remain poorly described. In this paper, we investigate the role of EMD in the C16-ceramide autophagy pathway. Ceramides are bioactive signalling molecules acting notably in the regulation of cell growth, differentiation or cell death. However, the mechanisms by which they mediate these pathways are not fully understood. We found that C16-ceramide induces EMD phosphorylation on its LEM domain through PRKACA. Upon ceramide treatment, phosphorylated EMD binds LC3 leading to an increase of the autophagosomes formation. These data suggest a new role of EMD as an enhancer of autophagosomes formation in the C16-ceramide autophagy pathway in colon cancer cells.
Research Center/Unit :
Giga-Signal Transduction - ULiège Centre Interfacultaire de Recherche du Médicament - CIRM
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Deroyer, Céline ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Renert, Anne-Françoise
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Fillet, Marianne ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Language :
English
Title :
New role for Emerin, a key inner nuclear membrane protein, as an enhancer of the autophagosome formation in the C16-ceramide autophagy pathway.
Publication date :
2014
Journal title :
Autophagy
ISSN :
1554-8627
eISSN :
1554-8635
Publisher :
Landes Bioscience, Georgetown, United States - Texas
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique ULg - Université de Liège
Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science 1996; 274:1855-9; PMID:8943189; http://dx.doi.org/10.1126/ science.274.5294.1855
Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004; 4:604-16; PMID:15286740; http://dx.doi.org/10.1038/nrc1411
Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 2013; 13:51-65; PMID:23235911; http://dx.doi.org/10.1038/nrc3398
Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science 1993; 259:1769-71; PMID:8456305; http://dx.doi.org/10.1126/science.8456305
Pettus BJ, Chalfant CE, Hannun YA. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta 2002; 1585:114-25; PMID:12531544; http://dx.doi.org/10.1016/S1388-1981(02)00331-1
Siskind LJ. Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr 2005; 37:143-53; PMID:16167171; http://dx.doi.org/10.1007/ s10863-005-6567-7
Mullen TD, Obeid LM. Ceramide and apoptosis: exploring the enigmatic connections between sphingolipid metabolism and programmed cell death. Anticancer Agents Med Chem 2012; 12:340-63; PMID:21707511; http://dx.doi.org/10. 2174/187152012800228661
Lavieu G, Scarlatti F, Sala G, Levade T, Ghidoni R, Botti J, Codogno P. Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision? Autophagy 2007; 3:45-7; PMID:17035732
Bedia C, Levade T, Codogno P. Regulation of autophagy by sphingolipids. Anticancer Agents Med Chem 2011; 11:844-53; PMID:21707487; http://dx.doi.org/10. 2174/187152011797655131
Quan W, Lim YM, Lee MS. Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells. Exp Mol Med 2012; 44:81-8; PMID:22257883; http://dx.doi.org/10.3858/emm.2012.44.2.030
Sridhar S, Botbol Y, Macian F, Cuervo AM. Autophagy and disease: always two sides to a problem. J Pathol 2012; 226:255-73; PMID:21990109; http://dx.doi.org/10.1002/path.3025
Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, Vandewalle A, Ghidoni R, Codogno P. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 2004; 279:18384-91; PMID:14970205; http://dx.doi.org/10.1074/jbc.M313561200
Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004; 64:4286-93; PMID:15205343; http://dx.doi.org/10.1158/0008-5472.CAN-03-3084
Pattingre S, Bauvy C, Levade T, Levine B, Codogno P. Ceramide-induced autophagy: to junk or to protect cells? Autophagy 2009; 5:558-60; PMID:19337026; http://dx.doi.org/10.4161/auto.5.4.8390
Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B, Codogno P. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J Biol Chem 2009; 284:2719-28; PMID:19029119; http://dx.doi.org/10.1074/jbc. M805920200
Spassieva SD, Mullen TD, Townsend DM, Obeid LM. Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem J 2009; 424:273-83; PMID:19728861; http://dx.doi.org/10.1042/ BJ20090699
Rénert AF, Leprince P, Dieu M, Renaut J, Raes M, Bours V, Chapelle JP, Piette J, Merville MP, Fillet M. The proapoptotic C16-ceramide-dependent pathway requires the death-promoting factor Btf in colon adenocarcinoma cells. J Proteome Res 2009; 8:4810-22; PMID:19705920; http://dx.doi.org/10.1021/ pr9005316
Haraguchi T, Holaska JM, Yamane M, Koujin T, Hashiguchi N, Mori C, Wilson KL, Hiraoka Y. Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy. Eur J Biochem 2004; 271:1035-45; PMID:15009215; http://dx.doi.org/10.1111/j.1432-1033.2004.04007.x
Lin F, Blake DL, Callebaut I, Skerjanc IS, Holmer L, McBurney MW, Paulin-Levasseur M, Worman HJ. MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J Biol Chem 2000; 275:4840-7; PMID:10671519; http://dx.doi.org/10.1074/jbc.275.7.4840
Laguri C, Gilquin B, Wolff N, Romi-Lebrun R, Courchay K, Callebaut I, Worman HJ, Zinn-Justin S. Structural characterization of the LEM motif common to three human inner nuclear membrane proteins. Structure 2001; 9:503-11; PMID:11435115; http://dx.doi.org/10.1016/S0969-2126(01)00611-6
Haraguchi T, Koujin T, Segura-Totten M, Lee KK, Matsuoka Y, Yoneda Y, Wilson KL, Hiraoka Y. BAF is required for emerin assembly into the reforming nuclear envelope. J Cell Sci 2001; 114:4575-85; PMID:11792822
Lee KK, Haraguchi T, Lee RS, Koujin T, Hiraoka Y, Wilson KL. Distinct functional domains in emerin bind lamin A and DNA-bridging protein BAF. J Cell Sci 2001; 114:4567-73; PMID:11792821
Segura-Totten M, Kowalski AK, Craigie R, Wilson KL. Barrier-to- autointegration factor: major roles in chromatin decondensation and nuclear assembly. J Cell Biol 2002; 158:475-85; PMID:12163470; http://dx.doi.org/10. 1083/jcb.200202019
Furukawa K, Sugiyama S, Osouda S, Goto H, Inagaki M, Horigome T, Omata S, McConnell M, Fisher PA, Nishida Y. Barrier-to-autointegration factor plays crucial roles in cell cycle progression and nuclear organization in Drosophila. J Cell Sci 2003; 116:3811-23; PMID:12902403; http://dx.doi.org/10.1242/jcs.00682
Margalit A, Vlcek S, Gruenbaum Y, Foisner R. Breaking and making of the nuclear envelope. J Cell Biochem 2005; 95:454-65; PMID:15832341; http://dx.doi.org/10.1002/jcb.20433
Wang X, Xu S, Rivolta C, Li LY, Peng GH, Swain PK, Sung CH, Swaroop A, Berson EL, Dryja TP, et al. Barrier to autointegration factor interacts with the cone-rod homeobox and represses its transactivation function. J Biol Chem 2002; 277:43288-300; PMID:12215455; http://dx.doi.org/10.1074/jbc.M207952200
Holaska JM, Lee KK, Kowalski AK, Wilson KL. Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro. J Biol Chem 2003; 278:6969-75; PMID:12493765; http://dx.doi.org/10.1074/jbc.M208811200
Fairley EA, Kendrick-Jones J, Ellis JA. The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. J Cell Sci 1999; 112:2571-82; PMID:10393813
Clements L, Manilal S, Love DR, Morris GE. Direct interaction between emerin and lamin A. Biochem Biophys Res Commun 2000; 267:709-14; PMID:10673356; http://dx.doi.org/10.1006/bbrc.1999.2023
Holaska JM, Wilson KL. An emerin "proteome": purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechanosensing, and nuclear architecture. Biochemistry 2007; 46:8897-908; PMID:17620012; http://dx.doi.org/10.1021/bi602636m
Demmerle J, Koch AJ, Holaska JM. The nuclear envelope protein emerin binds directly to histone deacetylase 3 (HDAC3) and activates HDAC3 activity. J Biol Chem 2012; 287:22080-8; PMID:22570481; http://dx.doi.org/10.1074/jbc.M111. 325308
Muchir A, Pavlidis P, Bonne G, Hayashi YK, Worman HJ. Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy. Hum Mol Genet 2007; 16:1884-95; PMID:17567779; http://dx.doi.org/10.1093/hmg/ddm137
Muchir A, Pavlidis P, Decostre V, Herron AJ, Arimura T, Bonne G, Worman HJ. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J Clin Invest 2007; 117:1282-93; PMID:17446932; http://dx.doi.org/10.1172/JCI29042
Ellis JA, Craxton M, Yates JR, Kendrick-Jones J. Aberrant intracellular targeting and cell cycle-dependent phosphorylation of emerin contribute to the Emery-Dreifuss muscular dystrophy phenotype. J Cell Sci 1998; 111:781-92; PMID:9472006
Hirano Y, Segawa M, Ouchi FS, Yamakawa Y, Furukawa K, Takeyasu K, Horigome T. Dissociation of emerin from barrier-to-autointegration factor is regulated through mitotic phosphorylation of emerin in a xenopus egg cell-free system. J Biol Chem 2005; 280:39925-33; PMID:16204256; http://dx.doi.org/10. 1074/jbc.M503214200
Roberts RC, Sutherland-Smith AJ, Wheeler MA, Jensen ON, Emerson LJ, Spiliotis II, Tate CG, Kendrick-Jones J, Ellis JA. The Emery-Dreifuss muscular dystrophy associated-protein emerin is phosphorylated on serine 49 by protein kinase A. FEBS J 2006; 273:4562-75; PMID:16972941; http://dx.doi.org/10.1111/j. 1742-4658.2006.05464.x
Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol 2005; 23:94-101; PMID:15592455; http://dx.doi.org/10.1038/nbt1046
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2006; 127:635-48; PMID:17081983; http://dx.doi.org/10.1016/j. cell.2006.09.026
Schlosser A, Amanchy R, Otto H. Identification of tyrosine- phosphorylation sites in the nuclear membrane protein emerin. FEBS J 2006; 273:3204-15; PMID:16857009; http://dx.doi.org/10.1111/j.1742-4658.2006.05329.x
Tifft KE, Bradbury KA, Wilson KL. Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases. J Cell Sci 2009; 122:3780-90; PMID:19789182; http://dx.doi.org/10.1242/jcs.048397
Yip SC, Cotteret S, Chernoff J. Sumoylated protein tyrosine phosphatase 1B localizes to the inner nuclear membrane and regulates the tyrosine phosphorylation of emerin. J Cell Sci 2012; 125:310-6; PMID:22266903; http://dx.doi.org/10.1242/jcs.086256
Morris JB, Hofemeister H, O'Hare P. Herpes simplex virus infection induces phosphorylation and delocalization of emerin, a key inner nuclear membrane protein. J Virol 2007; 81:4429-37; PMID:17301149; http://dx.doi.org/10. 1128/JVI.02354-06
Leach N, Bjerke SL, Christensen DK, Bouchard JM, Mou F, Park R, Baines J, Haraguchi T, Roller RJ. Emerin is hyperphosphorylated and redistributed in herpes simplex virus type 1-infected cells in a manner dependent on both UL34 and US3. J Virol 2007; 81:10792-803; PMID:17652388; http://dx.doi.org/10.1128/ JVI.00196-07
Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva MYu, Obeid LM, Hannun YA. Role for ceramide in cell cycle arrest. J Biol Chem 1995; 270:2047-52; PMID:7836432; http://dx.doi.org/10.1074/jbc.270.5.2047
Bandyopadhyay U, Cuervo AM. Chaperone-mediated autophagy in aging and neurodegeneration: lessons from alpha-synuclein. Exp Gerontol 2007; 42:120-8; PMID:16860504; http://dx.doi.org/10.1016/j.exger.2006.05.019
Mizushima N. Autophagy: process and function. Genes Dev 2007; 21:2861-73; PMID:18006683; http://dx.doi.org/10.1101/gad.1599207
Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson KL, Morris GE. Emerin interacts in vitro with the splicing-associated factor, YT521-B. Eur J Biochem 2003; 270:2459-66; PMID:12755701; http://dx.doi.org/10.1046/j.1432-1033.2003.03617.x
Holaska JM, Kowalski AK, Wilson KL. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol 2004; 2:E231; PMID:15328537; http://dx.doi.org/10.1371/journal.pbio. 0020231
Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Körner R, Greff Z, Kéri G, Stemmann O, Mann M. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 2008; 31:438-48; PMID:18691976; http://dx.doi.org/10.1016/j.molcel.2008.07.007
Pan C, Gnad F, Olsen JV, Mann M. Quantitative phosphoproteome analysis of a mouse liver cell line reveals specificity of phosphatase inhibitors. Proteomics 2008; 8:4534-46; PMID:18846507; http://dx.doi.org/10.1002/pmic. 200800105
Amanchy R, Kalume DE, Iwahori A, Zhong J, Pandey A. Phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture (SILAC). J Proteome Res 2005; 4:1661-71; PMID:16212419; http://dx.doi.org/10.1021/pr050134h
Dbaibo GS. Regulation of the stress response by ceramide. Biochem Soc Trans 1997; 25:557-61; PMID:9191155
Plo I, Ghandour S, Feutz AC, Clanet M, Laurent G, Bettaieb A. Involvement of de novo ceramide biosynthesis in lymphotoxin-induced oligodendrocyte death. Neuroreport 1999; 10:2373-6; PMID:10439466; http://dx.doi.org/10.1097/00001756- 199908020-00028
Levy JM, Thorburn A. Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol Ther 2011; 131:130-41; PMID:21440002; http://dx.doi.org/10.1016/j.pharmthera.2011.03.009
Hu YL, Jahangiri A, Delay M, Aghi MK. Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res 2012; 72:4294-9; PMID:22915758; http://dx.doi.org/10.1158/0008-5472. CAN-12-1076
Palumbo S, Comincini S. Autophagy and ionizing radiation in tumors: the "survive or not survive" dilemma. J Cell Physiol 2013; 228:1-8; PMID:22585676; http://dx.doi.org/10.1002/jcp.24118
Koukourakis MI, Giatromanolaki A, Sivridis E, Pitiakoudis M, Gatter KC, Harris AL. Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia. Br J Cancer 2010; 103:1209-14; PMID:20842118; http://dx.doi.org/10.1038/sj.bjc.6605904
Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 2008; 98:923-30; PMID:18319715; http://dx.doi.org/10.1038/sj. bjc.6604269
Park MA, Zhang G, Norris J, Hylemon PB, Fisher PB, Grant S, Dent P. Regulation of autophagy by ceramide-CD95-PERK signaling. Autophagy 2008; 4:929-31; PMID:18719356
Yacoub A, Hamed HA, Allegood J, Mitchell C, Spiegel S, Lesniak MS, Ogretmen B, Dash R, Sarkar D, Broaddus WC, et al. PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells. Cancer Res 2010; 70:1120-9; PMID:20103619; http://dx.doi.org/10.1158/0008-5472.CAN-09-4043
Bhutia SK, Dash R, Das SK, Azab B, Su ZZ, Lee SG, Grant S, Yacoub A, Dent P, Curiel DT, et al. Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24. Cancer Res 2010; 70:3667-76; PMID:20406981; http://dx.doi.org/10.1158/0008-5472.CAN-09-3647
Ito H, Murakami M, Furuhata A, Gao S, Yoshida K, Sobue S, Hagiwara K, Takagi A, Kojima T, Suzuki M, et al. Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta 2009; 1789:681-90; PMID:19698806; http://dx.doi.org/10.1016/j.bbagrm.2009.08.006
Olshefski RS, Ladisch S. Glucosylceramide synthase inhibition enhances vincristine-induced cytotoxicity. Int J Cancer 2001; 93:131-8; PMID:11391632; http://dx.doi.org/10.1002/ijc.1301
Guenther GG, Peralta ER, Rosales KR, Wong SY, Siskind LJ, Edinger AL. Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc Natl Acad Sci U S A 2008; 105:17402-7; PMID:18981422; http://dx.doi.org/ 10.1073/pnas.0802781105
Park YE, Hayashi YK, Bonne G, Arimura T, Noguchi S, Nonaka I, Nishino I. Autophagic degradation of nuclear components in mammalian cells. Autophagy 2009; 5:795-804; PMID:19550147
