Our Research

The role of ubiquitin and ubiquitin-like molecules in cellular stress responses

The family of ubiquitin and ubiquitin-like molecules (Ubls), such as SUMO and NEDD8, consists of small proteins that control almost every biological process, from protein destruction to regulation of transcription, subcellular localization, DNA repair, endocytosis, signal transduction and autophagy. This vast functional diversity is due to the ability of this family of proteins to covalently modify other proteins and alter their function. The importance of ubiquitin and Ubls is also highlighted by the fact that many compounds that target the ubiquitin pathway are in clinical trials or already used for cancer treatment. Therefore, it is critical to understand the role of these pathways in cell physiology and pathology.
Our research is focussed on NEDD8, which is important for cell viability, growth and development. Our goal is to identify NEDD8 targets and to understand how the NEDD8 pathway is controlled, especially in conditions of cellular stress. We combine biochemical, biological, quantitative proteomic and genetic approaches (C. elegans) to address these questions. As NEDD8 pathway inhibitors are currently tested in clinical trials for cancer treatment, our research will contribute towards optimization of their therapeutic use.

L'agence nationale de la recherche | Université de Rennes 1 | Université de Rennes 1

2021

  • Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis. Serrano-Maciá M, Simón J, González-Rellan MJ, Azkargorta M, Goikoetxea-Usandizaga N, Lopitz-Otsoa F, De Urturi DS, Rodríguez-Agudo R, Lachiondo-Ortega S, Mercado-Gomez M, Gutiérrez de Juan V, Bizkarguenaga M, Fernández-Ramos D, Buque X, Baselli GA, Valenti LVC, Iruzubieta P, Crespo J, Villa E, Banales JM, Avila MA, Marin JJG, Aspichueta P, Sutherland J, Barrio R, Mayor U, Elortza F, Xirodimas DP, Nogueiras R, Delgado TC, Martínez-Chantar ML. Mol Metab. 101275 Pubmed
  • The HSP70 chaperone as sensor of the NEDD8 cycle upon DNA damage. Bailly AP, Xirodimas DP. Biochem Soc Trans. 49(3):1075-1083. Pubmed
  • Proteome-wide identification of NEDD8 modification sites reveals distinct proteomes for canonical and atypical NEDDylation. Sofia Lobato-Gil, Jan B. Heidelberger, Chantal Maghames, Aymeric Bailly, Lorene Brunello, Manuel S. Rodriguez, Petra Beli, and Dimitris P. Xirodimas. Cell Rep. 34(3):108635. Pubmed

2020

  • Development of Nanobodies as first-in-class inhibitors for the NEDP1 deNEDDylating enzyme. Naima Abidi, Helene Trauchessec, Gholamreza Hassanzadeh-Ghassabeh, Martine Pugniere, Serge Muyldermans, Dimitris P. Xirodimas. bioRxiv 2020.03.20.999326 Pubmed
  • Antibody RING-Mediated Destruction of Endogenous Proteins. Ibrahim AFM, Shen L, Tatham MH, Dickerson D, Prescott AR, Abidi N, Xirodimas DP, Hay RT. Mol Cell ; S1097-2765(20)30274-4. Pubmed

2019

  • The balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity. Bailly AP, Perrin A, Serrano-Macia M, Maghames C, Leidecker O, Trauchessec H, Martinez-Chantar ML, Gartner A, Xirodimas DP. Cell Rep. 29(1):212-224 Pubmed

2018

  • NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress. Maghames CM, Lobato-Gil S, Perrin A, Trauchessec H, Rodriguez MS, Urbach S, Marin P, Xirodimas DP. Nat Commun. 9(1):4376. Pubmed
  • Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function. El Motiam A, Vidal S, de la Cruz-Herrera CF, Da Silva-Álvarez S, Baz-Martínez M, Seoane R, Vidal A, Rodríguez MS, Xirodimas DP, Carvalho AS, Beck HC, Matthiesen R, Collado M, Rivas C. FASEB J. :fj201800341RR Pubmed

2017

  • Quantitative FLIM-FRET Microscopy to Monitor Nanoscale Chromatin Compaction In Vivo Reveals Structural Roles of Condensin Complexes. Llères D, Bailly AP, Perrin A, Norman DG, Xirodimas DP, Feil R. Cell Rep. 18:1791-1803. Pubmed

2016

  • The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity. Malhab LJ, Descamps S, Delaval B, Xirodimas DP. Sci Rep. 6:37775. Pubmed
  • The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Bailly A, Perrin A, Bou Malhab LJ, Pion E, Larance M, Nagala M, Smith P, O’Donohue MF, Gleizes PE, Zomerdijk J, Lamond AI, Xirodimas DP. 35:415-26. Pubmed

2015

  • PKA-dependent phosphorylation of ribosomal protein S6 does not correlate with translation efficiency in striatonigral and striatopallidal medium-sized spiny neurons. Biever A, Puighermanal E, Nishi A, David A, Panciatici C, Longueville S, Xirodimas D, Gangarossa G, Meyuhas O, Hervé D, Girault JA, Valjent E. J Neurosci. 35:4113-30. Pubmed
  • Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic. Abidi N, Xirodimas DP. Endocr Relat Cancer. 22:T55-70. Pubmed

2013

  • DNA-binding regulates site-specific ubiquitination of IRF-1. Landré V, Pion E, Narayan V, Xirodimas DP, Ball KL. Biochem J. 449(3):707-17. Pubmed
  • DUBs « found in translation »: USP15 controls stability of newly synthesized REST. Xirodimas DP. Cell Cycle. 12(16):2536-7. Pubmed

2012

  • Characterization of MRFAP1 turnover and interactions downstream of the NEDD8 pathway. Larance M, Kirkwood KJ, Xirodimas DP, Lundberg E, Uhlen M, Lamond AI. Mol Cell Proteomics. 11(3):M111.014407. Pubmed
  • Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. Embade N, Fernández-Ramos D, Varela-Rey M, Beraza N, Sini M, Gutiérrez de Juan V, Woodhoo A, Martínez-López N, Rodríguez-Iruretagoyena B, Bustamante FJ, de la Hoz AB, Carracedo A, Xirodimas DP, Rodríguez MS, Lu SC, Mato JM, Martínez-Chantar ML. 55(4):1237-48. Pubmed
  • Isolation of NEDDylated proteins in human cells. Leidecker O, Xirodimas DP. Methods Mol Biol. 832:133-40. Pubmed
  • The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions. Leidecker O, Matic I, Mahata B, Pion E, Xirodimas DP. Cell Cycle. 11(6):1142-50. Pubmed
  • The p53 isoforms are differentially modified by Mdm2. Camus S, Ménendez S, Fernandes K, Kua N, Liu G, Xirodimas DP, Lane DP, Bourdon JC. Cell Cycle.11(8):1646-55. Pubmed
  • Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from spatio-temporal modelling. Sturrock M, Terry AJ, Xirodimas DP, Thompson AM, Chaplain MA. Bull Math Biol. 74(7):1531-79. Pubmed

2011

  • Spatio-temporal modelling of the Hes1 and p53-Mdm2 intracellular signalling pathways. Sturrock M, Terry AJ, Xirodimas DP, Thompson AM, Chaplain MA. J Theor Biol. 273(1):15-31. Pubmed
  • The essential functions of NEDD8 are mediated via distinct surface regions, and not by polyneddylation in Schizosaccharomyces pombe. Girdwood D, Xirodimas DP, Gordon C. PLoS One. 6(5):e20089. Pubmed
  • In the family with ubiquitin. Alexandru G, Pariente N, Xirodimas D. EMBO Rep. 12(9):880-2. Pubmed
  • Stable-isotope labeling with amino acids in nematodes. Larance M, Bailly AP, Pourkarimi E, Hay RT, Buchanan G, Coulthurst S, Xirodimas DP, Gartner A, Lamond AI. Nat Methods. 8(10):849-51. Pubmed

2010

  • Perturbation of 60 S ribosomal biogenesis results in ribosomal protein L5- and L11-dependent p53 activation. Sun XX, Wang YG, Xirodimas DP, Dai MS. J Biol Chem. 285(33):25812-21. Pubmed
  • Mechanism of hypoxia-induced NF-kappaB. Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S. Mol Cell Biol. 30(20):4901-21. Pubmed
  • Ubiquitin Family Members in the Regulation of the Tumor Suppressor p53. Xirodimas DP, Scheffner M. Subcell Biochem. 54:116-35. Pubmed

2009

  • Regulation of nucleolar signalling to p53 through NEDDylation of L11. Sundqvist A, Liu G, Mirsaliotis A, Xirodimas DP. EMBO Rep. 10(10):1132-9. Pubmed
  • Detection of protein SUMOylation in vivo. Tatham MH, Rodriguez MS, Xirodimas DP, Hay RT. Nat Protoc. 4(9):1363-71. Pubmed

2008

  • Ribosomal proteins are targets for the NEDD8 pathway. Xirodimas DP, Sundqvist A, Nakamura A, Shen L, Botting C, Hay RT. EMBO Rep. 9(3):280-6. Pubmed
  • Much to know about proteolysis: intricate proteolytic machineries compromise essential cellular functions. Marfany G, Farràs R, Salido E, Xirodimas DP, Rodríguez MS. Biochem Soc Trans. 36(Pt 5):781-5. Pubmed
  • Novel substrates and functions for the ubiquitin-like molecule NEDD8. Xirodimas DP. Biochem Soc Trans. 36(Pt 5):802-6. Pubmed

Ubiquitin/Ubiquitin-like molecules and Protein Quality Control

Dimitris XIRODIMAS

Group Leader (Research Director DR2)

Team Members

  • Aymeric BAILLY
    (CRCN) +33 (0)4 34 35 95 34
  • Léo LE TAREAU Autre
    (Doctorant) +33 (0)4 34 35 95 33
  • Jolanta POLANOWSKA
    (CRCN) +33 (0)4 34 35 95 33
  • Rohit SHRIVASTAVA
    (Post-Doc) +33 (0)4 34 35 95 34
  • Helene TRAUCHESSEC
    (AI-Recherche) +33 (0)4 34 35 95 33
  • Dimitris XIRODIMAS Chef d'équipe
    (Chercheur DR2) +33 (0)4 34 35 95 33
  • Contact us

    Replace the name and address below with that of the member to contact
    Firstname.name@crbm.cnrs.fr

    OUR PUBLICATIONS

    Proteome-wide identification of NEDD8 modification sites reveals distinct proteomes for canonical and atypical NEDDylation.

    Lobato-Gil S, Heidelberger JB, Maghames C, Bailly A, Brunello L, Rodriguez MS, Beli P, Xirodimas DP.

    Cell Rep. 2021 Jan 19;34(3):108635.

    Pubmed

    The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity.

    Bailly AP, Perrin A, Serrano-Macia M, Maghames C, Leidecker O, Trauchessec H, Martinez-Chantar ML, Gartner A, Xirodimas DP.

    Cell Rep. 2019 Oct 1;29(1):212-224.e8.

    Pubmed

    NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress.

    Maghames CM, Lobato-Gil S, Perrin A, Trauchessec H, Rodriguez MS, Urbach S, Marin P, Xirodimas DP.

    Nat Commun. 2018 Oct 22;9(1):4376.

    Pubmed