Ubiquitin/Ubiquitin-like molecules and Protein Quality Control

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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.

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Dimitris Xirodimas

Members of the team

  • Aymeric BAILLY
    (Staff Scientist) +33 (0)4 34 35 95 34
  • Lorene BRUNELLO
    (PhD Student) +33 (0)4 34 35 95 34
  • Igor MESZKA
    (PhD Student) +33 (0)4 34 35 95 34
  • Jolanta POLANOWSKA
    (Staff Scientist) +33 (0)4 34 35 95 33
    (Post-Doc) +33 (0)4 34 35 95 34
    (Research Assistant) +33 (0)4 34 35 95 33
  • Dimitris XIRODIMAS Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 33
    • 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

    • 2020

      Antibody RING-Mediated Destruction of Endogenous Proteins

      Adel F M Ibrahim, Linnan Shen, Michael H Tatham, David Dickerson, Alan R Prescott, Naima Abidi, Dimitris P Xirodimas, Ronald[...]

      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

    • 2018

      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,[...]

      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

    • 2016

      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[...]

      Oncogene. 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,[...]

      J Neurosci. 35:4113-30. Pubmed

    • 2015

      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

    • 2013

      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

    • 2012

      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,[...]

      Hepatology. 55(4):1237-48. Pubmed

    • 2012

      Isolation of NEDDylated proteins in human cells.

      Leidecker O, Xirodimas DP.

      Methods Mol Biol. 832:133-40. Pubmed

    • 2012

      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

    • 2012

      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

    • 2012

      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

    • 2011

      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

    • 2011

      In the family with ubiquitin.

      Alexandru G, Pariente N, Xirodimas D.

      EMBO Rep. 12(9):880-2. Pubmed

    • 2011

      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

    • 2010

      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

    • 2010

      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

    • 2009

      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

    • 2008

      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

    • 2008

      Novel substrates and functions for the ubiquitin-like molecule NEDD8.

      Xirodimas DP.

      Biochem Soc Trans. 36(Pt 5):802-6. Pubmed

    NEDD8 as a sensor of cellular stress-cross-talk with the ubiquitin pathway
    While many data are available on the role of NEDD8 in homeostatic conditions, through regulation of Cullin-Ring-Ligases and other targets, our knowledge on the NEDD8 pathway function in stress conditions remains very limited. Our previous work on the nucleolus, the centre for ribosome biogenesis, revealed one of the very first examples of how the NEDD8 pathway responds to cellular stress. By combining NEDD8 proteomics and studies in human cells and in C. elegans, we showed that NEDDylation controls the nucleolar proteome composition and that many ribosomal proteins (RPs) are direct NEDD8 targets  (Xirodimas, 2008; Bailly et al., 2016). Upon DNA damage-induced nucleolar stress, NEDDylation of many RPs is decreased, allowing their localization to the nucleoplasm and activation of the p53 tumour suppressor (Sundqvist et al., 2009). Analysis of molecular events at the chromatin level shows that RPs are recruited at promoter sites of p53-regulated genes and promote the additional recruitment of p53 transcriptional co-activators (CBP/p300) (Mahata et al., 2012).

    We recently revealed a more diverse response of the NEDD8 pathway in different stress conditions. Specifically, NEDDylation rapidly increases in response to inhibition of the 26S proteasome activity, heat shock and oxidative stress. However, stress-induced NEDD8 conjugation is mediated by enzymes of the ubiquitin rather than of the NEDD8 pathway. This was quite surprising, as it was widely believed that each conjugation pathway has its unique set of E1, E2 and E3 enzymes that lead to specific activation and conjugation of their cognate molecules. Thus, our findings define a new mode of protein NEDDylation in stress conditions. By developing proteomic approaches, we could demonstrate that substrate proteins are modified with poly-NEDD8 or mixed NEDD8-ubiquitin chains upon stress. These studies revealed a potential new role for NEDD8 as sensor of cellular stress and an unprecedented cross-talk between the NEDD8 and ubiquitin pathways in stress conditions (Leidecker et al., 2012).