[en] Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation.
Lebraud, Emilie; Institut de Radioprotection et de Sûreté Nucléaire Laboratoire de radiobiologie des Expositions Médicales (IRSN), Fontenay-aux-Roses, France
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation
Date de publication/diffusion :
31 octobre 2022
Titre du périodique :
Frontiers in Oncology
eISSN :
2234-943X
Maison d'édition :
Frontiers Media, Lausanne, Suisse
Volume/Tome :
12
Fascicule/Saison :
958155
Peer reviewed :
Peer reviewed vérifié par ORBi
Projet FnR :
FNR15850547 - Pink1-related Molecular Mechanisms To Dissect The Connection Between Type 2 Diabetes And Insulin Resistance In Parkinson'S Disease, 2021 (01/01/2022-31/08/2024) - Giuseppe Arena
Giacomello M Pyakurel A Glytsou C and Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol (2020) 21(4):204–24. doi: 10.1038/s41580-020-0210-7
Eramo MJ Lisnyak V Formosa LE and Ryan MT. The ‘mitochondrial contact site and cristae organising system’(MICOS) in health and human disease. J Biochem (2020) 167(3):243–55. doi: 10.1093/jb/mvz111
Modjtahedi N Tokatlidis K Dessen P and Kroemer G. Mitochondrial proteins containing coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) domains in health and disease. Trends Biochem Sci (2016) 41(3):245–60. doi: 10.1016/j.tibs.2015.12.004
Vance JE. Inter-organelle membrane contact sites: implications for lipid metabolism. Biol Direct (2020) 15(1):24. doi: 10.1186/s13062-020-00279-y
Reane DV Rizzuto R and Raffaello A. The ER-mitochondria tether at the hub of Ca2+ signaling. Curr Opin Physiol (2020) 17:261–8. doi: 10.1016/j.cophys.2020.08.013
Habich M Salscheider SL Riemer J. Cysteine residues in mitochondrial intermembrane space proteins: More than just import. Br J Pharmacol (2019) 176(4):514–31. doi: 10.1111/bph.14480
Reinhardt C Arena G Nedara K Edwards R Brenner C Tokatlidis K et al. AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway. Biochim Biophys Acta Mol Basis Dis (2020) 1866(6):165746. doi: 10.1016/j.bbadis.2020.165746
Zhou ZD Saw WT Tan EK. Mitochondrial CHCHD-containing proteins: Physiologic functions and link with neurodegenerative diseases. Mol Neurobiol (2017) 54(7):5534–46. doi: 10.1007/s12035-016-0099-5
Dimmer KS Fritz S Fuchs F Messerschmitt M Weinbach N Neupert W et al. Genetic basis of mitochondrial function and morphology in saccharomyces cerevisiae. Mol Biol Cell (2002) 13(3):847–53. doi: 10.1091/mbc.01-12-0588
Gabriel K Milenkovic D Chacinska A Muller J Guiard B Pfanner N et al. Novel mitochondrial intermembrane space proteins as substrates of the MIA import pathway. J Mol Biol (2007) 365(3):612–20. doi: 10.1016/j.jmb.2006.10.038
Longen S Bien M Bihlmaier K Kloeppel C Kauff F Hammermeister M et al. Systematic analysis of the twin cx(9)c protein family. J Mol Biol (2009) 393(2):356–68. doi: 10.1016/j.jmb.2009.08.041
Cavallaro G. Genome-wide analysis of eukaryotic twin CX9C proteins. Mol Biosyst (2010) 6(12):2459–70. doi: 10.1039/c0mb00058b
Park WR Nakamura Y. p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway. Cancer Res (2005) 65(4):1197–206. doi: 10.1158/0008-5472.CAN-04-3339
Sesaki H Dunn CD Iijima M Shepard KA Yaffe MP Machamer CE et al. Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J Cell Biol (2006) 173(5):651–8. doi: 10.1083/jcb.200603092
Potting C Wilmes C Engmann T Osman C Langer T. Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. EMBO J (2010) 29(17):2888–98. doi: 10.1038/emboj.2010.169
Tamura Y Iijima M Sesaki H. Mdm35p imports ups proteins into the mitochondrial intermembrane space by functional complex formation. EMBO J (2010) 29(17):2875–87. doi: 10.1038/emboj.2010.149
Tatsuta T Langer T. Intramitochondrial phospholipid trafficking. Biochim Biophys Acta (2017) 1862(1):81–9. doi: 10.1016/j.bbalip.2016.08.006
Miliara X Garnett JA Tatsuta T Abid Ali F Baldie H Perez-Dorado I et al. Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes. EMBO Rep (2015) 16(7):824–35. doi: 10.15252/embr.201540229
Watanabe Y Tamura Y Kawano S Endo T. Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria. Nat Commun (2015) 6:7922. doi: 10.1038/ncomms8922
Yu F He F Yao H Wang C Wang J Li J et al. Structural basis of intramitochondrial phosphatidic acid transport mediated by Ups1-Mdm35 complex. EMBO Rep (2015) 16(7):813–23. doi: 10.15252/embr.201540137
Connerth M Tatsuta T Haag M Klecker T Westermann B Langer T. Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. Science (2012) 338(6108):815–8. doi: 10.1126/science.1225625
Tamura Y Kawano S Endo T. Lipid homeostasis in mitochondria. Biol Chem (2020) 401(6-7):821–33. doi: 10.1515/hsz-2020-0121
Paradies G Paradies V Ruggiero FM Petrosillo G. Cardiolipin and mitochondrial function in health and disease. Antioxid Redox Signal (2014) 20(12):1925–53. doi: 10.1089/ars.2013.5280
Aaltonen MJ Friedman JR Osman C Salin B di Rago JP Nunnari J et al. MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J Cell Biol (2016) 213(5):525–34. doi: 10.1083/jcb.201602007
Miyata N Watanabe Y Tamura Y Endo T and Kuge O. Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria. J Cell Biol (2016) 214(1):77–88. doi: 10.1083/jcb.201601082
Potting C Tatsuta T Konig T Haag M Wai T Aaltonen MJ and Langer T. TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab (2013) 18(2):287–95. doi: 10.1016/j.cmet.2013.07.008
Miliara X Matthews S. Structural comparison of yeast and human intra-mitochondrial lipid transport systems. Biochem Soc Trans (2016) 44(2):479–85. doi: 10.1042/BST20150264
Miliara X Tatsuta T Berry JL Rouse SL Solak K Chorev DS et al. Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins. Nat Commun (2019) 10(1):1130. doi: 10.1038/s41467-019-09089-x
Andrysik Z Kim J Tan AC and Espinosa JM. A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation. Cell Rep (2013) 3(5):1346–54. doi: 10.1016/j.celrep.2013.04.014
Felix RS Colleoni GW Caballero OL Yamamoto M Almeida MS Andrade VC et al. SAGE analysis highlights the importance of p53csv, ddx5, mapkapk2 and ranbp2 to multiple myeloma tumorigenesis. Cancer Lett (2009) 278(1):41–8. doi: 10.1016/j.canlet.2008.12.022
Li Y Tang X He Q Yang X Ren X Wen X et al. Overexpression of mitochondria mediator gene TRIAP1 by miR-320b loss is associated with progression in nasopharyngeal carcinoma. PloS Genet (2016) 12(7):e1006183. doi: 10.1371/journal.pgen.1006183
Zhang J COng R Zhao K Wang Y Song N and Gu M. High TRIAP1 expression in penile carcinoma is associated with high risk of recurrence and poor survival. Ann Trans Med (2019) 7(14). doi: 10.21037/atm.2019.06.47
Uhlen M Zhang C Lee S Sjostedt E Fagerberg L Bidkhori G et al. A pathology atlas of the human cancer transcriptome. Science (2017) 357(6352):eaan2507. doi: 10.1126/science.aan2507
Bunz F Hwang PM Torrance C Waldman T Zhang Y Dillehay L et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest (1999) 104(3):263–9. doi: 10.1172/JCI6863
Rousselle C Barbier M Comte VV Alcouffe C Clement-Lacroix J Chancel G et al. Innocuousness and intracellular distribution of PKH67: A fluorescent probe for cell proliferation assessment. Vitro Cell Dev Biol Anim (2001) 37(10):646–55. doi: 10.1290/1071-2690(2001)037<0646:IAIDOP>2.0.CO;2
Vrieling M Santema W Van Rhijn I Rutten V Koets A. γδ T cell homing to skin and migration to skin-draining lymph nodes is CCR7 independent. J Immunol (2012) 188(2):578–84. doi: 10.4049/jimmunol.1101972
Deerinck TJ Bushong EA Thor A Ellisman MH. NCMIR methods for 3D EM: a new protocol for preparation of biological specimens for serial block face scanning electron microscopy. Microscopy (2010) 1:6–8.
Walton J. Lead asparate, an en bloc contrast stain particularly useful for ultrastructural enzymology. J Histochem Cytochem (1979) 27(10):1337–42. doi: 10.1177/27.10.512319
Kremer JR Mastronarde DN McIntosh JR. Computer visualization of three-dimensional image data using IMOD. J Struct Biol (1996) 116(1):71–6. doi: 10.1006/jsbi.1996.0013
Chen J Bardes EE Aronow BJ Jegga AG. ToppGene suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res (2009) 37(Web Server issue):W305–311. doi: 10.1093/nar/gkp427
Seyer A Boudah S Broudin S Junot C Colsch B. Annotation of the human cerebrospinal fluid lipidome using high resolution mass spectrometry and a dedicated data processing workflow. Metabolomics (2016) 12(5):1–14. doi: 10.1007/s11306-016-1023-8
Kessner D Chambers M Burke R Agus D Mallick P. ProteoWizard: Open source software for rapid proteomics tools development. Bioinformatics (2008) 24(21):2534–6. doi: 10.1093/bioinformatics/btn323
Giacomoni F Le Corguille G Monsoor M Landi M Pericard P Petera M et al. Workflow4Metabolomics: A collaborative research infrastructure for computational metabolomics. Bioinformatics (2015) 31(9):1493–5. doi: 10.1093/bioinformatics/btu813
Boudah S Olivier MF Aros-Calt S Oliveira L Fenaille F Tabet JC et al. Annotation of the human serum metabolome by coupling three liquid chromatography methods to high-resolution mass spectrometry. J Chromatogr B Analyt Technol BioMed Life Sci (2014) 966:34–47. doi: 10.1016/j.jchromb.2014.04.025
Sumner LW Amberg A Barrett D Beale MH Beger R Daykin CA et al. Proposed minimum reporting standards for chemical analysis. Metabolomics (2007) 3(3):211–21. doi: 10.1007/s11306-007-0082-2
Benit P Goncalves S Philippe Dassa E Briere JJ Martin G Rustin P. Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta (2006) 374(1-2):81–6. doi: 10.1016/j.cca.2006.05.034
Rustin P Chretien D Bourgeron T Gerard B Rotig A Saudubray JM et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta (1994) 228(1):35–51. doi: 10.1016/0009-8981(94)90055-8
Weinberg F Hamanaka R Wheaton WW Weinberg S Joseph J Lopez M et al. Mitochondrial metabolism and ROS generation are essential for kras-mediated tumorigenicity. Proc Natl Acad Sci USA (2010) 107(19):8788–93. doi: 10.1073/pnas.1003428107
Robinson BH Petrova-Benedict R Buncic JR Wallace DC. Nonviability of cells with oxidative defects in galactose medium: A screening test for affected patient fibroblasts. Biochem Med Metab Biol (1992) 48(2):122–6. doi: 10.1016/0885-4505(92)90056-5
Petrova-Benedict R Buncic JR Wallace DC Robinson BH. Selective killing of cells with oxidative defects in galactose medium: a screening test for affected patient fibroblasts. J Inherit Metab Dis (1992) 15(6):943–4. doi: 10.1007/BF01800243
Marroquin LD Hynes J Dykens JA Jamieson JD Will Y. Circumventing the crabtree effect: Replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci (2007) 97(2):539–47. doi: 10.1093/toxsci/kfm052
Gohil VM Sheth SA Nilsson R Wojtovich AP Lee JH Perocchi F et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol (2010) 28(3):249–55. doi: 10.1038/nbt.1606
Xia J Wishart DS. Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst. Nat Protoc (2011) 6(6):743–60. doi: 10.1038/nprot.2011.319
Jacquemyn J Cascalho A Goodchild RE. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep (2017) 18(11):1905–21. doi: 10.15252/embr.201643426
Thomas PD Campbell MJ Kejariwal A Mi H Karlak B Daverman R et al. PANTHER: A library of protein families and subfamilies indexed by function. Genome Res (2003) 13(9):2129–41. doi: 10.1101/gr.772403
Waldman T Kinzler KW Vogelstein B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res (1995) 55(22):5187–90.
Shamloo B Usluer S. p21 in cancer research. Cancers (Basel) (2019) 11(8):1178. doi: 10.3390/cancers11081178
Budanov AV. Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal (2011) 15(6):1679–90. doi: 10.1089/ars.2010.3530
Kruiswijk F Labuschagne CF Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol (2015) 16(7):393–405. doi: 10.1038/nrm4007
Labuschagne CF Zani F Vousden KH. Control of metabolism by p53 - cancer and beyond. Biochim Biophys Acta Rev Cancer (2018) 1870(1):32–42. doi: 10.1016/j.bbcan.2018.06.001
Cetinbas NM Sudderth J Harris RC Cebeci A Negri GL Yılmaz ÖH et al. Glucose-dependent anaplerosis in cancer cells is required for cellular redox balance in the absence of glutamine. Sci Rep (2016) 6(1):1–12. doi: 10.1038/srep32606
Tajan M Hock AK Blagih J Robertson NA Labuschagne CF Kruiswijk F et al. A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metab (2018). doi: 10.1136/esmoopen-2018-EACR25.43
Lowman XH Hanse EA Yang Y Gabra MBI Tran TQ Li H et al. p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake. Cell Rep (2019) 26(11):3051–3060.e3054. doi: 10.1016/j.celrep.2019.02.037
Tardito S Oudin A Ahmed SU Fack F Keunen O Zheng L et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol (2015) 17(12):1556–68. doi: 10.1038/ncb3272
Allen MA Andrysik Z Dengler VL Mellert HS Guarnieri A Freeman JA et al. Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms. eLife (2014) 3:e02200. doi: 10.7554/eLife.02200.019
Adams C Cazzanelli G Rasul S Hitchinson B Hu Y Coombes RC et al. Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance. Oncol Rep (2015) 34(1):415–22. doi: 10.3892/or.2015.3988
Osman C Haag M Potting C Rodenfels J Dip PV Wieland FT et al. The genetic interactome of prohibitins: Coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria. J Cell Biol (2009) 184(4):583–96. doi: 10.1083/jcb.200810189
Tamura Y Endo T Iijima M Sesaki H. Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria. J Cell Biol (2009) 185(6):1029–45. doi: 10.1083/jcb.200812018
Miyata N Goda N Matsuo K Hoketsu T Kuge O. Cooperative function of Fmp30, Mdm31, and Mdm32 in Ups1-independent cardiolipin accumulation in the yeast saccharomyces cerevisiae. Sci Rep (2017) 7(1):16447. doi: 10.1038/s41598-017-16661-2
Miyata N Fujii S and Kuge O. Porin proteins have critical functions in mitochondrial phospholipid metabolism in yeast. J Biol Chem (2018) 293(45):17593–605. doi: 10.1074/jbc.RA118.005410
Eiyama A Aaltonen MJ Nolte H Tatsuta T Langer T. Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling. J Biol Chem (2021) 100335. doi: 10.1016/j.jbc.2021.100335
Chandel NS. Mitochondria as signaling organelles. BMC Biol (2014) 12:34. doi: 10.1186/1741-7007-12-34
Quiros PM Mottis A Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol (2016) 17(4):213–26. doi: 10.1038/nrm.2016.23
Qureshi MA Haynes CM Pellegrino MW. The mitochondrial unfolded protein response: Signaling from the powerhouse. J Biol Chem (2017) 292(33):13500–6. doi: 10.1074/jbc.R117.791061
Aubrey BJ Kelly GL Janic A Herold MJ Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differentiation (2018) 25(1):104–13. doi: 10.1038/cdd.2017.169
Lacroix M Riscal R Arena G Linares LK Le Cam L. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. Mol Metab (2020) 33:2–22. doi: 10.1016/j.molmet.2019.10.002
Jones RG Plas DR Kubek S Buzzai M Mu J Xu Y et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell (2005) 18(3):283–93. doi: 10.1016/j.molcel.2005.03.027
Maddocks OD Berkers CR Mason SM Zheng L Blyth K Gottlieb E et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature (2013) 493(7433):542–6. doi: 10.1038/nature11743
Reid MA Wang W-I Rosales KR Welliver MX Pan M Kong M. The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol Cell (2013) 50(2):200–11. doi: 10.1016/j.molcel.2013.02.008
Tran TQ Lowman XH Reid MA Mendez-Dorantes C Pan M Yang Y et al. Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene (2017) 36(14):1991–2001. doi: 10.1038/onc.2016.360
