Advertisement

The SEACIT complex is involved in the maintenance of vacuole–mitochondria contact sites and controls mitophagy

  • Yinxing Ma
  • Alexis Moors
  • Nadine Camougrand
  • Svetlana DokudovskayaEmail author
Original Article
First Online:

Abstract

The major signaling pathway that regulates cell growth and metabolism is under the control of the target of rapamycin complex 1 (TORC1). In Saccharomyces cerevisiae the SEA complex is one of the TORC1 upstream regulators involved in amino acid sensing and autophagy. Here, we performed analysis of the expression, interactions and localization of SEA complex proteins under different conditions, varying parameters such as sugar source, nitrogen availability and growth phase. Our results show that the SEA complex promotes mitochondria degradation either by mitophagy or by general autophagy. In addition, the SEACIT subcomplex is involved in the maintenance of the vacuole–mitochondria contact sites. Thus, the SEA complex appears to be an important link between the TORC1 pathway and regulation of mitochondria quality control.

Keywords

Membrane contact sites Vacuole Mitochondria SEA complex TORC1 Autophagy Mitophagy 

Abbreviations

ROS

Reactive oxygen species

SEACAT

SEA subcomplex activating TORC1

SEACIT

SEA subcomplex inhibiting TORC1

TORC1

Target of rapamycin complex 1

vCLAMPs

Vacuole–mitochondria contact sites

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

We are grateful to Jaclyn Tetenbaum-Novatt and Renaud Legouis for critical reading of manuscript. We thank Sebastien Leon, Christian Ungermann, Benedikt Westermann and Claudio de Virgilio for sharing plasmids and antibodies.

Funding

SD acknowledge financial support from La Ligue contre le Cancer (Comité de Paris/Ile-de-France and Comité d’Oise), PICS USA (CNRS); YM is grateful to the support from Chinese Scholarship Council (CSC). We thank Proteomic Core Facility (support from grants TA2013 and TA2016), Imaging and Cytometry Facility (PFIC, UMS CNRS 3655—INSERM US23, support from grant TA2017).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests

Supplementary material

18_2019_3015_MOESM1_ESM.tif (1.2 mb)
Supplementary material 1 (TIFF 1200 kb)
18_2019_3015_MOESM2_ESM.pdf (5.2 mb)
Supplementary material 2 (PDF 5340 kb)
18_2019_3015_MOESM3_ESM.pdf (55 kb)
Supplementary material 3 (PDF 55 kb)
18_2019_3015_MOESM4_ESM.pdf (10.4 mb)
Supplementary material 4 (PDF 10604 kb)
18_2019_3015_MOESM5_ESM.pdf (1.2 mb)
Supplementary material 5 (PDF 1274 kb)
18_2019_3015_MOESM6_ESM.pdf (3.6 mb)
Supplementary material 6 (PDF 3688 kb)
18_2019_3015_MOESM7_ESM.pdf (7.9 mb)
Supplementary material 7 (PDF 8120 kb)
18_2019_3015_MOESM8_ESM.pdf (3.1 mb)
Supplementary material 8 (PDF 3125 kb)
18_2019_3015_MOESM9_ESM.pdf (3.1 mb)
Supplementary material 9 (PDF 3151 kb)
18_2019_3015_MOESM10_ESM.docx (142 kb)
Supplementary material 10 (DOCX 142 kb)
18_2019_3015_MOESM11_ESM.docx (135 kb)
Supplementary material 11 (DOCX 135 kb)
18_2019_3015_MOESM12_ESM.docx (99 kb)
Supplementary material 12 (DOCX 99 kb)
18_2019_3015_MOESM13_ESM.xlsx (39 kb)
Supplementary material 13 (XLSX 38 kb)
18_2019_3015_MOESM14_ESM.xlsx (183 kb)
Supplementary material 14 (XLSX 182 kb)
18_2019_3015_MOESM15_ESM.xlsx (45 kb)
Supplementary material 15 (XLSX 45 kb)

References

  1. 1.
    Loewith R, Hall MN (2011) Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189(4):1177–1201.  https://doi.org/10.1534/genetics.111.133363 Google Scholar
  2. 2.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293.  https://doi.org/10.1016/j.cell.2012.03.017 Google Scholar
  3. 3.
    Huang K, Fingar DC (2014) Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol 36:79–90.  https://doi.org/10.1016/j.semcdb.2014.09.011 Google Scholar
  4. 4.
    Ruetenik A, Barrientos A (2015) Dietary restriction, mitochondrial function and aging: from yeast to humans. Biochem Biophys Acta 1847 11:1434–1447.  https://doi.org/10.1016/j.bbabio.2015.05.005 Google Scholar
  5. 5.
    Groenewoud MJ, Zwartkruis FJ (2013) Rheb and mammalian target of rapamycin in mitochondrial homoeostasis. Open Biol 3(12):130185.  https://doi.org/10.1098/rsob.130185 Google Scholar
  6. 6.
    Li M, Zhao L, Liu J, Liu A, Jia C, Ma D, Jiang Y, Bai X (2010) Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 22(10):1469–1476.  https://doi.org/10.1016/j.cellsig.2010.05.015 Google Scholar
  7. 7.
    Kawai S, Urban J, Piccolis M, Panchaud N, De Virgilio C, Loewith R (2011) Mitochondrial genomic dysfunction causes dephosphorylation of Sch9 in the yeast Saccharomyces cerevisiae. Eukaryot Cell 10(10):1367–1369.  https://doi.org/10.1128/EC.05157-11 Google Scholar
  8. 8.
    Jazwinski SM, Kriete A (2012) The yeast retrograde response as a model of intracellular signaling of mitochondrial dysfunction. Front Physiol 3:139.  https://doi.org/10.3389/fphys.2012.00139 Google Scholar
  9. 9.
    Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos DP, Cristea IM, Williams R, Salamero J, Chait BT, Sali A, Field MC, Rout MP, Dargemont C (2011) A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol Cell Proteomics 10(6):M110006478.  https://doi.org/10.1074/mcp.m110.006478 Google Scholar
  10. 10.
    Dokudovskaya S, Rout MP (2011) A novel coatomer-related SEA complex dynamically associates with the vacuole in yeast and is implicated in the response to nitrogen starvation. Autophagy 7(11):1392–1393.  https://doi.org/10.4161/auto.7.11.17347 Google Scholar
  11. 11.
    Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM (2013) A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340(6136):1100–1106.  https://doi.org/10.1126/science.1232044 Google Scholar
  12. 12.
    Panchaud N, Peli-Gulli MP, De Virgilio C (2013) SEACing the GAP that nEGOCiates TORC1 activation: evolutionary conservation of Rag GTPase regulation. Cell Cycle 12(18):1–5.  https://doi.org/10.4161/cc.26000 Google Scholar
  13. 13.
    Dokudovskaya S, Rout MP (2015) SEA you later alli-GATOR—a dynamic regulator of the TORC1 stress response pathway. J Cell Sci 128(12):2219–2228.  https://doi.org/10.1242/jcs.168922 Google Scholar
  14. 14.
    Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24(7):400–406.  https://doi.org/10.1016/j.tcb.2014.03.003 Google Scholar
  15. 15.
    Powis K, De Virgilio C (2016) Conserved regulators of Rag GTPases orchestrate amino acid-dependent TORC1 signaling. Cell Discov 2:15049.  https://doi.org/10.1038/celldisc.2015.49 Google Scholar
  16. 16.
    Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, Sevier CS, Ding H, Koh JL, Toufighi K, Mostafavi S, Prinz J, St Onge RP, VanderSluis B, Makhnevych T, Vizeacoumar FJ, Alizadeh S, Bahr S, Brost RL, Chen Y, Cokol M, Deshpande R, Li Z, Lin ZY, Liang W, Marback M, Paw J, San Luis BJ, Shuteriqi E, Tong AH, van Dyk N, Wallace IM, Whitney JA, Weirauch MT, Zhong G, Zhu H, Houry WA, Brudno M, Ragibizadeh S, Papp B, Pal C, Roth FP, Giaever G, Nislow C, Troyanskaya OG, Bussey H, Bader GD, Gingras AC, Morris QD, Kim PM, Kaiser CA, Myers CL, Andrews BJ, Boone C (2010) The genetic landscape of a cell. Science 327(5964):425–431.  https://doi.org/10.1126/science.1180823 Google Scholar
  17. 17.
    Costanzo M, VanderSluis B, Koch EN, Baryshnikova A, Pons C, Tan G, Wang W, Usaj M, Hanchard J, Lee SD, Pelechano V, Styles EB, Billmann M, van Leeuwen J, van Dyk N, Lin ZY, Kuzmin E, Nelson J, Piotrowski JS, Srikumar T, Bahr S, Chen Y, Deshpande R, Kurat CF, Li SC, Li Z, Usaj MM, Okada H, Pascoe N, San Luis BJ, Sharifpoor S, Shuteriqi E, Simpkins SW, Snider J, Suresh HG, Tan Y, Zhu H, Malod-Dognin N, Janjic V, Przulj N, Troyanskaya OG, Stagljar I, Xia T, Ohya Y, Gingras AC, Raught B, Boutros M, Steinmetz LM, Moore CL, Rosebrock AP, Caudy AA, Myers CL, Andrews B, Boone C (2016) A global genetic interaction network maps a wiring diagram of cellular function. Science.  https://doi.org/10.1126/science.aaf1420 Google Scholar
  18. 18.
    Algret R, Fernandez-Martinez J, Shi Y, Kim SJ, Pellarin R, Cimermancic P, Cochet E, Sali A, Chait BT, Rout MP, Dokudovskaya S (2014) Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway. Mol Cell Proteomics 13(11):2855–2870.  https://doi.org/10.1074/mcp.M114.039388 Google Scholar
  19. 19.
    Elbaz-Alon Y, Rosenfeld-Gur E, Shinder V, Futerman AH, Geiger T, Schuldiner M (2014) A dynamic interface between vacuoles and mitochondria in yeast. Dev Cell 30(1):95–102.  https://doi.org/10.1016/j.devcel.2014.06.007 Google Scholar
  20. 20.
    Merz S, Westermann B (2009) Genome-wide deletion mutant analysis reveals genes required for respiratory growth, mitochondrial genome maintenance and mitochondrial protein synthesis in Saccharomyces cerevisiae. Genome Biol 10(9):R95.  https://doi.org/10.1186/gb-2009-10-9-r95 Google Scholar
  21. 21.
    Honscher C, Mari M, Auffarth K, Bohnert M, Griffith J, Geerts W, van der Laan M, Cabrera M, Reggiori F, Ungermann C (2014) Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev Cell 30(1):86–94.  https://doi.org/10.1016/j.devcel.2014.06.006 Google Scholar
  22. 22.
    Alber F, Dokudovskaya S, Veenhoff LM, Zhang W, Kipper J, Devos D, Suprapto A, Karni-Schmidt O, Williams R, Chait BT, Rout MP, Sali A (2007) Determining the architectures of macromolecular assemblies. Nature 450(7170):683–694.  https://doi.org/10.1038/nature06404 Google Scholar
  23. 23.
    Neklesa TK, Davis RW (2009) A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex. PLoS Genet 5(6):e1000515.  https://doi.org/10.1371/journal.pgen.1000515 Google Scholar
  24. 24.
    LaCava J, Molloy KR, Taylor MS, Domanski M, Chait BT, Rout MP (2015) Affinity proteomics to study endogenous protein complexes: pointers, pitfalls, preferences and perspectives. Biotechniques 58(3):103–119.  https://doi.org/10.2144/000114262 Google Scholar
  25. 25.
    Brosch M, Yu L, Hubbard T, Choudhary J (2009) Accurate and sensitive peptide identification with Mascot Percolator. J Proteome Res 8(6):3176–3181.  https://doi.org/10.1021/pr800982s Google Scholar
  26. 26.
    Kurihara Y, Kanki T, Aoki Y, Hirota Y, Saigusa T, Uchiumi T, Kang D (2012) Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem 287(5):3265–3272.  https://doi.org/10.1074/jbc.M111.280156 Google Scholar
  27. 27.
    Wu X, Tu BP (2011) Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Mol Biol Cell 22(21):4124–4133.  https://doi.org/10.1091/mbc.E11-06-0525 Google Scholar
  28. 28.
    Chong YT, Koh JL, Friesen H, Duffy SK, Cox MJ, Moses A, Moffat J, Boone C, Andrews BJ (2015) Yeast proteome dynamics from single cell imaging and automated analysis. Cell 161(6):1413–1424.  https://doi.org/10.1016/j.cell.2015.04.051 Google Scholar
  29. 29.
    Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O’Shea EK (2003) Global analysis of protein localization in budding yeast. Nature 425(6959):686–691.  https://doi.org/10.1038/nature02026nature02026 Google Scholar
  30. 30.
    Gonzalez Montoro A, Auffarth K, Honscher C, Bohnert M, Becker T, Warscheid B, Reggiori F, van der Laan M, Frohlich F, Ungermann C (2018) Vps39 interacts with Tom40 to establish one of two functionally distinct vacuole-mitochondria contact sites. Dev cell 45(5):621-636 e627.  https://doi.org/10.1016/j.devcel.2018.05.011 Google Scholar
  31. 31.
    Lang AB, John Peter AT, Walter P, Kornmann B (2015) ER-mitochondrial junctions can be bypassed by dominant mutations in the endosomal protein Vps13. J Cell Biol 210(6):883–890.  https://doi.org/10.1083/jcb.201502105 Google Scholar
  32. 32.
    John Peter AT, Herrmann B, Antunes D, Rapaport D, Dimmer KS, Kornmann B (2017) Vps13-Mcp1 interact at vacuole-mitochondria interfaces and bypass ER-mitochondria contact sites. J Cell Biol.  https://doi.org/10.1083/jcb.201610055 Google Scholar
  33. 33.
    Binda M, Peli-Gulli MP, Bonfils G, Panchaud N, Urban J, Sturgill TW, Loewith R, De Virgilio C (2009) The Vam6 GEF controls TORC1 by activating the EGO complex. Mol Cell 35(5):563–573.  https://doi.org/10.1016/j.molcel.2009.06.033 Google Scholar
  34. 34.
    Kuzmin E, VanderSluis B, Wang W, Tan G, Deshpande R, Chen Y, Usaj M, Balint A, Mattiazzi Usaj M, van Leeuwen J, Koch EN, Pons C, Dagilis AJ, Pryszlak M, Wang JZY, Hanchard J, Riggi M, Xu K, Heydari H, San Luis BJ, Shuteriqi E, Zhu H, Van Dyk N, Sharifpoor S, Costanzo M, Loewith R, Caudy A, Bolnick D, Brown GW, Andrews BJ, Boone C, Myers CL (2018) Systematic analysis of complex genetic interactions. Science.  https://doi.org/10.1126/science.aao1729 Google Scholar
  35. 35.
    van Leeuwen J, Pons C, Mellor JC, Yamaguchi TN, Friesen H, Koschwanez J, Usaj MM, Pechlaner M, Takar M, Usaj M, VanderSluis B, Andrusiak K, Bansal P, Baryshnikova A, Boone CE, Cao J, Cote A, Gebbia M, Horecka G, Horecka I, Kuzmin E, Legro N, Liang W, van Lieshout N, McNee M, San Luis BJ, Shaeri F, Shuteriqi E, Sun S, Yang L, Youn JY, Yuen M, Costanzo M, Gingras AC, Aloy P, Oostenbrink C, Murray A, Graham TR, Myers CL, Andrews BJ, Roth FP, Boone C (2016) Exploring genetic suppression interactions on a global scale. Science.  https://doi.org/10.1126/science.aag0839 Google Scholar
  36. 36.
    Usaj M, Tan Y, Wang W, VanderSluis B, Zou A, Myers CL, Costanzo M, Andrews B, Boone C (2017) TheCellMap.org: a web-accessible database for visualizing and mining the global yeast genetic interaction network. G3 (Bethesda) 7(5):1539–1549.  https://doi.org/10.1534/g3.117.040220 Google Scholar
  37. 37.
    Panchaud N, Peli-Gulli MP, De Virgilio C (2013) Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal 6(277):ra42.  https://doi.org/10.1126/scisignal.2004112 Google Scholar
  38. 38.
    Deffieu M, Bhatia-Kissova I, Salin B, Klionsky DJ, Pinson B, Manon S, Camougrand N (2013) Increased levels of reduced cytochrome b and mitophagy components are required to trigger nonspecific autophagy following induced mitochondrial dysfunction. J Cell Sci 126(Pt 2):415–426.  https://doi.org/10.1242/jcs.103713 Google Scholar
  39. 39.
    Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441(2):523–540.  https://doi.org/10.1042/BJ20111451 Google Scholar
  40. 40.
    Pan Y, Schroeder EA, Ocampo A, Barrientos A, Shadel GS (2011) Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab 13(6):668–678.  https://doi.org/10.1016/j.cmet.2011.03.018 Google Scholar
  41. 41.
    Graef M, Nunnari J (2011) Mitochondria regulate autophagy by conserved signalling pathways. EMBO J 30(11):2101–2114.  https://doi.org/10.1038/emboj.2011.104 Google Scholar
  42. 42.
    Sutter BM, Wu X, Laxman S, Tu BP (2013) Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154(2):403–415.  https://doi.org/10.1016/j.cell.2013.06.041 Google Scholar
  43. 43.
    Kira S, Tabata K, Shirahama-Noda K, Nozoe A, Yoshimori T, Noda T (2014) Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy. Autophagy 10(9):1565–1578.  https://doi.org/10.4161/auto.29397 Google Scholar
  44. 44.
    Laxman S, Sutter BM, Shi L, Tu BP (2014) Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites. Sci Signal 7(356):ra120.  https://doi.org/10.1126/scisignal.2005948 Google Scholar
  45. 45.
    Laxman S, Sutter BM, Wu X, Kumar S, Guo X, Trudgian DC, Mirzaei H, Tu BP (2013) Sulfur amino acids regulate translational capacity and metabolic homeostasis through modulation of tRNA thiolation. Cell 154(2):416–429.  https://doi.org/10.1016/j.cell.2013.06.043 Google Scholar
  46. 46.
    Klionsky DJ (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1):1–222.  https://doi.org/10.1080/15548627.2015.1100356 Google Scholar
  47. 47.
    Abeliovich H, Zarei M, Rigbolt KT, Youle RJ, Dengjel J (2013) Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy. Nat Commun 4:2789.  https://doi.org/10.1038/ncomms3789 Google Scholar
  48. 48.
    Sugiura A, McLelland GL, Fon EA, McBride HM (2014) A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J 33(19):2142–2156.  https://doi.org/10.15252/embj.201488104 Google Scholar
  49. 49.
    Kissova I, Salin B, Schaeffer J, Bhatia S, Manon S, Camougrand N (2007) Selective and non-selective autophagic degradation of mitochondria in yeast. Autophagy 3(4):329–336Google Scholar
  50. 50.
    Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B (2017) Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168(1–2):224-238 e210.  https://doi.org/10.1016/j.cell.2016.11.042 Google Scholar
  51. 51.
    Liu Y, Okamoto K (2018) The TORC1 signaling pathway regulates respiration-induced mitophagy in yeast. Biochem Biophys Res Commun 502(1):76–83.  https://doi.org/10.1016/j.bbrc.2018.05.123 Google Scholar
  52. 52.
    Okamoto K, Kondo-Okamoto N, Ohsumi Y (2009) Mitochondria- anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell 17(1):87–97.  https://doi.org/10.1016/j.devcel.2009.06.013 Google Scholar
  53. 53.
    Kanki T, Wang K, Baba M, Bartholomew CR, Lynch-Day MA, Du Z, Geng J, Mao K, Yang Z, Yen WL, Klionsky DJ (2009) A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mol Biol Cell 20(22):4730–4738.  https://doi.org/10.1091/mbc.E09-03-0225 Google Scholar
  54. 54.
    Muller M, Kotter P, Behrendt C, Walter E, Scheckhuber CQ, Entian KD, Reichert AS (2015) Synthetic quantitative array technology identifies the Ubp3-Bre5 deubiquitinase complex as a negative regulator of mitophagy. Cell Rep 10(7):1215–1225.  https://doi.org/10.1016/j.celrep.2015.01.044 Google Scholar
  55. 55.
    Mao K, Wang K, Zhao M, Xu T, Klionsky DJ (2011) Two MAPK-signaling pathways are required for mitophagy in Saccharomyces cerevisiae. J Cell Biol 193(4):755–767.  https://doi.org/10.1083/jcb.201102092 Google Scholar
  56. 56.
    Algret R, Dokudovskaya S (2012) The SEA complex—the beginning. Biopolym Cell 28(N4):281–284Google Scholar
  57. 57.
    Li F, Wang F, Haraldson K, Protopopov A, Duh FM, Geil L, Kuzmin I, Minna JD, Stanbridge E, Braga E, Kashuba VI, Klein G, Lerman MI, Zabarovsky ER (2004) Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C. Cancer Res 64(18):6438–6443Google Scholar
  58. 58.
    Luc R, Tortorella SM, Ververis K, Karagiannis TC (2015) Lactate as an insidious metabolite due to the Warburg effect. Mol Biol Rep 42(4):835–840.  https://doi.org/10.1007/s11033-015-3859-9 Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.CNRS, UMR 8126, Université Paris-Sud 11, Institut Gustave RoussyVillejuifFrance
  2. 2.CNRS, IBGC, UMR 5095BordeauxFrance
  3. 3.Université de Bordeaux, IBGCBordeauxFrance

Personalised recommendations

Cite article

Buy options