Ubiquitin-like proteins in Development and Disease


Posttranslational modifications (PTM) by the members of the ubiquitin/ubiquitin-like (Ub/UbL) family are essential for cell survival and the proper function of the organism. Cell signalling drives conserved enzymatic pathways to add Ub/UbLs to other proteins,  determining the fate of a protein, including changes in its protein-protein interactions, localization or in its stability and degradation. Dysfunction of these modifications are implicated in many illnesses, including cancer, diabetes, neurodegeneration, as well as rare diseases. However, despite their importance, to study Ub/UbL modifications is particularly challenging because they are normally transient and occur in a small percentage of a given protein pool. We are interested on the role of Ubiquitin-like family members during development in fisiological conditions and in disease.


Tools to study Ubiquitin-likes

We developed SUMO-ID, a strategy to identify interactors of proteins when modified by Ubiquitin-likes. We tested the system with well known modified proteins, lile PML and p53, and with less studied proteins, like SALL1. The system is very specific and it works with other Ubiquitin-likes in addition to SUMO.





Identification of proximal SUMO-dependent interactors using SUMO-ID Orhi Barroso-Gomila, Fredrik Trulsson, Veronica Muratore, Iñigo Canosa, Laura Merino-Cacho, Ana Rosa Cortazar, Coralia Perez, Mikel Azkargorta, Ibon Iloro, Arkaitz Carracedo, Ana M Aransay, Felix Elortza, Ugo Mayor, Alfred C. O. Vertegaal, Rosa Barrio*, James D. Sutherland*

Nat Commun. 2021 Nov 18;12(1):6671. doi: 10.1038/s41467-021-26807-6. PMID: 34795231






We also developed a comprehensive toolbox for studying Ubiquitin-like modifications, consisting of a collection of DNA vectors that enable in vivo biotinylation and purification of target proteins. This flexible and easy-to-use toolbox can be used in cell lines, in patient-derived cells, and in transgenic animals.






Cellular distribution of indicated biotyilated Ubiquitin-likes in human cells visualized using fluorescently-labeled streptavidin. Adapted from: Pirone et al. A comprehensive platform for the analysis of ubiquitin-like protein modifications using in vivo biotinylation. Scientific Reports (2017) 7:40756. PMID: 28098257






Ubiquitin-likes in Development & Disease


Steroid hormones are cholesterol derivates that control many aspects of animal physiology, including development, growth, energy storage and reproduction. In Drosophila, pulses of the steroid hormone ecdysone precede molting and metamorphosis, the regulation of hormonal synthesis being a crucial step that determines animal viability and size. Low levels of the small ubiquitin-like modifier SUMO impede the synthesis of ecdysone, as SUMO is needed for cholesterol intake.





Schematic representation the Drosophila Ring Gland.

Adapted from: Talamillo A, Sánchez J, Cantera R, Pérez C, Martín D, Caminero E, Barrio R.  Smt3 is required for Drosophila melanogaster metamorphosis.  Development. 2008 May;135(9):1659-68. PMID: 18367553









We are interested on the role of Ubiquitin-like proteins in development and associated developmental diseases.



Ubiquitin-related Networks



> ProteoCure: A sound proteome for a sound body: targeting proteolysis for proteome remodeling





> Redes de Excelencia (Spanish MINECO) 2018-2020. UBIRed. Ubiquitin-like proteins in signaling, proliferation and cancer



> UbiCODE, ITN (EU) 2018-2021



COST (EU) 2014-2018




ITN (EU) 2011-2014

 

Publications on SUMO and Ubiquitin-likes

Other Laboratory Publications





Orhi Barroso-Gomila, Fredrik Trulsson, Veronica Muratore, Iñigo Canosa, Laura Merino-Cacho, Ana Rosa Cortazar, Coralia Perez, Mikel Azkargorta, Ibon Iloro, Arkaitz Carracedo, Ana M Aransay, Felix Elortza, Ugo Mayor, Alfred C. O. Vertegaal, Rosa Barrio*, James D. Sutherland*

Nat Commun. 2021 Nov 18;12(1):6671. doi: 10.1038/s41467-021-26807-6.

PMID: 34795231









Origin and Development of the Adipose Tissue, a Key Organ in Physiology and Disease

Parra-Peralbo E*, Talamillo A*, Barrio R.

Front. Cell Dev. Biol., 21 December 2021 doi: 10.3389/fcell.2021.786129









SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes.

Giordano I, Pirone L, Muratore V, Landaluze E, Pérez C, Lang V, Garde-Lapido E, Gonzalez-Lopez M, Barroso-Gomila O, Vertegaal ACO, Aransay AM, Rodriguez JA, Rodriguez MS, Sutherland JD*, Barrio R.*

Front Cell Dev Biol. 2021 Sep 21;9:715868. doi: 10.3389/fcell.2021.715868. eCollection 2021.

PMID: 34153521









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. 2021 Jun 18;53:101275. doi: 10.1016/j.molmet.2021.101275.

PMID: 34153521



LUZP1 controls cell division, migration and invasion through regulation of the actin cytoskeleton

Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Martín-Martín N, Ercilla A, Rodríguez JA, Carracedo A, Sutherland JD*, Barrio R.*

Front Cell Dev Biol. 2021 Apr 1;9:624089. doi: 10.3389/fcell.2021.624089.

PMID: 33869174










Virtual meeting, real and sound science: report of the 17 th Meeting of the Spanish Society for Developmental Biology (SEBD-2020)

Araújo SJ*, Almudi I, Bozal-Basterra L, Casares F, Casas-Tintó S, Escalante A, García-Moreno F, Losada-Pérez M, Maeso I, Marcon L, Ocaña O, Pampliega O, Rada-Iglesias Á, Rayon T, Sharpe J, Sutherland JD, Villa Del Campo C, Barrio R.*

Int J Dev Biol. 2021;65(7-8-9):457-464. doi: 10.1387/ijdb.210005rb.

PMID: 33501996




Role of Sumoylation in Neurodegenerative Diseases and Inflammation

Esmeralda Parra-Peralbo, Veronica Muratore, Orhi Barroso-Gomila, Ana Talamillo, James D. Sutherland, Rosa Barrio*

Oxidative Stress and Disease book series edited by Enrique Cadenas and Helmut Sies on Proteostasis, CRC Press, Taylor & Francis Group. doi: 10.1201/9781003048138-8.

ISBN: 9781003048138










Proteostasis and Disease: From Basic Mechanisms to Clinics

Editors: Rosa Barrio, James D. Sutherland, Manuel S. Rodriguez

Advances in Experimental Medicine and Biology (AEMB, volume 1233), 2020, Springer. doi: 10.1007/978-3-030-38266-7.

ISBN: 9783030382650; ISBN: 9783030382667








Multi-omics integration highlights the role of ubiquitination in CCl4-induced liver fibrosis

Mercado-Gómez M, Lopitz-Otsoa F, Azkargorta M, Marina Serrano-Maciá , Sofia Lachiondo-Ortega , Naroa Goikoetxea-Usandizaga, Rubén Rodríguez-Agudo , David Fernández-Ramos , Maider Bizkarguenaga, Virginia Gutiérrez-de Juan , Benoît Lectez , Kerman Aloria, Jesus M Arizmendi,  Jorge Simon , Cristina Alonso, Juan J Lozano , Matias A Avila , Jesus M Banales , Jose J G Marin , Naiara Beraza , José M Mato , Felix Elortza , Rosa Barrio , James D Sutherland , Ugo Mayor , Maria L Martinez-Chantar *, Teresa C Delgado *

Int J Mol Sci. 2020 Nov 27;21(23):9043. doi: 10.3390/ijms21239043.

PMID: 33261190



LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome.

Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Bermejo-Arteagabeitia A, Da Fonseca C, Barroso-Gomila O, Azkargorta M, Iloro I, Pampliega O, Andrade R, Martín-Martín N, Branon TC, Ting AY, Rodríguez JA, Carracedo A, Elortza F, Sutherland JD*, Barrio R.*

Elife. 2020 Jun 18;9:e55957. doi: 10.7554/eLife.55957.

PMID: 32553112









Talamillo A*, Ajuria L, Grillo M, Barroso-Gomila O, Mayor U, Barrio R.* 

Open Biol. 2020 May;10(5):200054. doi: 10.1098/rsob.200054. Epub 2020 May 6.

PMID: 32370667











HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

Palomo-Irigoyen M, Pérez-Andrés E, Iruarrizaga-Lejarreta M, Barreira-Manrique A, Tamayo-Caro M, Vila-Vecilla L, Moreno-Cugnon L, Beitia N, Medrano D, Fernández-Ramos D, Lozano JJ, Okawa S, Lavín JL, Martín-Martín N, Sutherland JD, de Juan VG, Gonzalez-Lopez M, Macías-Cámara N, Mosén-Ansorena D, Laraba L, Hanemann CO, Ercolano E, Parkinson DB, Schultz CW, Araúzo-Bravo MJ, Ascensión AM, Gerovska D, Iribar H, Izeta A, Pytel P, Krastel P, Provenzani A, Seneci P, Carrasco RD, Del Sol A, Martinez-Chantar ML, Barrio R, Serra E, Lazaro C, Flanagan AM, Gorospe M, Ratner N, Aransay AM, Carracedo A, Varela-Rey M, Woodhoo A.*

J Clin Invest. 2020 Jul 1;130(7):3848-3864. doi: 10.1172/JCI130379.

PMID: 32315290



The role of SUMOylation during development

Talamillo A*, Barroso-Gomila O, Giordano I, Ajuria L, Grillo M, Mayor U, Barrio R.*

Biochem Soc Trans. 2020 Apr 29;48(2):463-478. doi: 10.1042/BST20190390.

PMID: 32311032








Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Hermanova I, Zúñiga-García P, Caro-Maldonado A, Fernandez-Ruiz S, Salvador F, Martín-Martín N, Zabala-Letona A, Nuñez-Olle M, Torrano V, Camacho L, Lizcano JM, Talamillo A, Carreira S, Gurel B, Cortazar AR, Guiu M, López JI, Martinez-Romero A, Astobiza I, Valcarcel-Jimenez L, Lorente M, Arruabarrena-Aristorena A, Velasco G, Gomez-Muñoz A, Suárez-Cabrera C, Lodewijk I, Flores JM, Sutherland JD, Barrio R, de Bono JS, Paramio JM, Trka J, Graupera M, Gomis RR, Carracedo A.*

J Exp Med. 2020 Jun 1;217(6). pii: e20191787. doi: 10.1084/jem.20191787.

PMID: 32219437


Regulation of the Ebola virus VP24 protein by SUMO.

Vidal S, El Motiam A, Seoane R, Preitakaite V, Bouzaher YH, Gómez-Medina S, San Martín C, Rodríguez D, Rejas MT, Baz-Martínez M, Barrio R, Sutherland JD, Rodríguez MS, Muñoz-Fontela C, Rivas C.*

J Virol. 2019 Oct 9. pii: JVI.01687-19. doi: 10.1128/JVI.01687-19.

PMID: 31597768




Biotin-based approaches for the study of SUMO and Ubiquitin modifications

Sutherland JD*, Barroso O, Barrio R*

Sumoylation and Ubiquitination: Current and Emerging Concepts. Caister Academic Publishing. doi: 10.21775/9781912530120.07.

ISBN: 978-1-912530-12-0












Targeting PML in triple negative breast cancer elicits growth suppression and senescence.

Arreal L, Piva M, Fernández S, Revandkar A, Schaub-Clerigué A, Villanueva J, Zabala-Letona A, Pujana M, Astobiza I, Cortazar AR, Hermanova I, Bozal-Basterra L, Arruabarrena-Aristorena A, Crespo JR, Valcarcel-Jimenez L, Zúñiga-García P, Canals F, Torrano V, Barrio R, Sutherland JD, Alimonti A, Martin-Martin N, Carracedo A.*

Cell Death Differ. 2019 Oct 1. doi: 10.1038/s41418-019-0407-5.

PMID: 31570853





Semin Cell Dev Biol. 2019 Sep;93 special issue

Proteostasis



Semin Cell Dev Biol. 2019 Sep;93:97-99. doi: 10.1016/j.semcdb.2019.04.011. Epub 2019 Apr 21.

Proteostasis: The network behind the networks.

Barrio R, Sutherland JD.

PMID: 31004754



Semin Cell Dev Biol. (2018) pii: S1084-9521(18)30161-7. doi: 10.1016/j.semcdb.2018.10.007.

Impaired proteostasis in rare neurological diseases.

Osinalde N, Duarri A, Ramirez J, Barrio R, de Nanclares GP, Mayor U.

PMID: 30355526





Trends Biochem Sci. 2019 Feb 25. pii: S0968-0004(19)30020-9. doi: 10.1016/j.tibs.2019.01.011. [Epub ahead of print] Review.

Using Ubiquitin Binders to Decipher the Ubiquitin Code.

Mattern M, Sutherland J, Kadimisetty K, Barrio R, Rodriguez MS.

PMID: 30819414

















Trends Biochem Sci. 2019 Feb 15. pii: S0968-0004(19)30007-6. doi: 10.1016/j.tibs.2019.01.007.

PROTEOSTASIS: A European Network to Break Barriers and Integrate Science on Protein Homeostasis.

Dissmeyer N, Coux O, Rodriguez MS, Barrio R; Core Group Members of PROTEOSTASIS.

PMID: 30777377








Semin Cell Dev Biol. (2018) pii: S1084-9521(18)30161-7. doi: 10.1016/j.semcdb.2018.10.007.

Impaired proteostasis in rare neurological diseases.

Osinalde N, Duarri A, Ramirez J, Barrio R, de Nanclares GP, Mayor U.

PMID: 30355526



Circ Heart Fail. (2018) 11(10):e005455. doi: 10.1161/CIRCHEARTFAILURE.118.005455.

Putting the Stress on UFM1 (Ubiquitin-Fold Modifier 1).

Sutherland JD*, Barrio R*.

PMID: 30354403








Human Molecular Genetics (2018) 27(11):1955-1971. doi: 10.1093/hmg/ddy103.

Quantitative proteomics reveals neuronal ubiquitination of Rngo/Ddi1 and several proteasomal subunits by Ube3a, accounting for the complexity of Angelman syndrome.

Ramirez J, Lectez B, Osinalde N, Sivá M, Elu N, Aloria K, Procházková M, Perez C, Martínez-Hernández J, Barrio R, Grantz Šašková K, Arizmendi JM and Mayor U*

PMID: 29788202


Mol Neurodegener. 2017 Apr 11;12(1):29. doi: 10.1186/s13024-017-0170-3

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons.

Martinez A, Lectez B, Ramirez J, Popp O, Sutherland JD, Urbé S, Dittmar G, Clague MJ, Mayor U.

PMID: 28399880



Scientific Reports (2017) 7:40756. doi: 10.1038/srep40756

A comprehensive platform for the analysis of ubiquitin-like protein modifications using in vivo biotinylation

Pirone L, Xolalpa W, Sigurðsson JO, Ramirez J, Pérez C, González M, de Sabando AR, Elortza F, Rodriguez MS, Mayor U, Olsen JV, Barrio R*, Sutherland JD.*

PMID: 28098257



Nature Communications (2016) 24(7):12595. doi: 10.1038/ncomms12595

Stratification and therapeutic potential of PML in metastatic breast cancer.

Martín-Martín N, Piva M, Urosevic J, Aldaz P, Sutherland JD, ... Barrio R, Serra V, Vivanco MdM, Matheu A, Gomis RR, Carracedo A*

PMID: 27553708


SUMO (2016) Methods in Molecular Biology, Springer, 1475:109-21. doi: 10.1007/978-1-4939-6358-4_8

Using Biotinylated SUMO-Traps to Analyze SUMOylated Proteins.

Lang V, Da Silva-Ferrada E, Barrio R, Sutherland JD, Rodriguez MS*

PMID: 27631801


SUMO (2016) Methods in Molecular Biology, Springer, 1475:161-9. doi: 10.1007/978-1-4939-6358-4_12

Analysis of SUMOylated Proteins in Cells and In Vivo Using the bioSUMO Strategy.

Pirone L, Xolalpa W, Mayor U, Barrio R*, Sutherland JD*

PMID: 27631805


Proteostasis (2016) Methods in Molecular Biology, Springer, 1449:193-202. doi:10.1007/978-1-4939-3756-1_10

Isolation of ubiquitinated proteins to high purity from in vivo samples.

Ramirez J, Min M, Barrio R, Lindon C*, Mayor U*

PMID: 27613036





Molecular Biology & Evolution (2016) 33(2):568-84. doi: 10.1093/molbev/msv242

Evolution of SUMO function and chain formation in insects.

Ureña E, Pirone L, Chafino S, Pérez C, Sutherland JD, Lang V, Rodriguez MS, Lopitz-Otsoa F, Blanco F, Barrio R*, Martin D.*

PMID: 26538142





PLoS One (2015) 10(10):e0139083. doi: 10.1371/journal.pone.0139083. eCollection 2015.

Proteomic Analysis of the Ubiquitin Landscape in the Drosophila Embryonic Nervous System and the Adult Photoreceptor Cells.

Ramirez J, Martinez A, Lectez B, Lee SY, Franco M, Barrio R, Dittmar G, Mayor U*

PMID: 26460970


Scientific Reports (2015) 5: 12383. doi:10.1038/srep12383.

The steroid hormone ecdysone promotes imaginal discs growth in Drosophila melanogaster.

Herboso L, Oliveira MM Talamillo A, Pérez C, González M, Martin D, Sutherland JD, Shingleton AW, Mirth C and Barrio R.*

PMID: 26198204


Cell Death and Disease (2014) 5, e1399.

The RING ubiquitin E3 RNF114 interacts with A20 and modulates NF-κB activity and T cell activation

Rodriguez MS, Egaña I, Lopitz-Otsoa F, Aillet F, Dorronroso A, Lobato-Gil S, Ferrin I, Sutherland JD, Barrio R, Trigueros C and Lang V*.

PMID: 25165885


Molecular Oncology. (2014) pii: S1574-7891(14)00079-9.

Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity

Lang V, Pallara C, Zabala A, Lobato-Gil S, Lopitz-Otsoa F, Farrás R, Hjerpe R, Torres-Ramos M, Zabaleta L,  Blattner C, Hay RT, Barrio R, Carracedo A,  Fernandez-Recio J, Rodríguez MS, Aillet F.

PMID: 24816189


J Proteome Res. 13(6):3016-26. doi: 10.1021/pr5001913

Ubiquitin Profiling in Liver Using a Transgenic Mouse with Biotinylated Ubiquitin.

Lectez B, Migotti R, Lee SY, Ramirez J, Beraza N, Mansfield B, Sutherland JD, Martinez-Chantar ML, Dittmar G, Mayor U.

PMID: 24730562


Cell Mol Life Sci. 2014, 71(14):2747-58. doi: 10.1007/s00018-013-1526-7.

Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.

Lee SY, Ramirez J, Franco M, Lectez B, Gonzalez M, Barrio R, Mayor U.

PMID: 24292889



PLoS Genetics 2013, 9(4): e1003473. doi:10.1371/journal.pgen.1003473 (2013)

Scavenger Receptors Mediate the Role of SUMO and Ftz-f1 in Drosophila Steroidogenesis.

Talamillo A, Herboso L, Pirone L, Pérez C, González M, Sánchez J, Mayor U, Lopitz-Otsoa F, Rodriguez MS, Sutherland JD and Barrio R.

PMID: 23637637





Front Oncol. 2013, Aug 5;3:200. doi: 10.3389/fonc.2013.00200.

PML: Not all about Tumor Suppression

Martin-Martin N, Sutherland JD, Carracedo A.

PMID: 23936764



Sci. Rep. 2011;1:75

Generation of stable Drosophila cell lines using multicistronic vectors

González M, Martín-Ruíz I, Jiménez S, Pirone L, Barrio R, Sutherland JD

PMID: 22355594

Request our vectors HEREhttp://www.addgene.org/search/?q=sutherland&db=plasmidshttps://www.addgene.org/James_Sutherland/shapeimage_2_link_0



Int J Dev Biol. 2011;55(6):603-11.

Expression of the Scavenger Receptor Class B type I (SR-BI) family in Drosophila melanogaster.

Herboso L, Talamillo A, Pérez C, Barrio R.

PMID: 21948708


Biochem J. 2011 Sep 15;438(3):437-45.

Drosophila Sal and Salr are transcriptional repressors.

Sánchez J, Talamillo A, González M, Sánchez-Pulido L, Jiménez S, Pirone L, Sutherland JD, Barrio R.

PMID: 21689070





J Biol Chem. 2010 Aug 13;285(33):25841-9. Epub 2010 Jun 18.

Sumoylation modulates the activity of Spalt-like proteins during wing development in Drosophila.

Sánchez J, Talamillo A, Lopitz-Otsoa F, Pérez C, Hjerpe R, Sutherland JD, Herboso L, Rodríguez MS, Barrio R.

PMID: 20562097





Biochem Soc Trans. 2010 Feb;38(Pt 1):54-9.

SUMO and ubiquitin modifications during steroid hormone synthesis and function.

Talamillo A, Martín D, Hjerpe R, Sánchez J, Barrio R.

PMID: 20074035


Biochem Soc Trans. 2008 Oct;36(Pt 5):868-73.

Functional analysis of the SUMOylation pathway in Drosophila.

Talamillo A, Sánchez J, Barrio R.

PMID: 18793153


Development. 2008 May;135(9):1659-68. Epub 2008 Mar 26.

Smt3 is required for Drosophila melanogaster metamorphosis.

Talamillo A, Sánchez J, Cantera R, Pérez C, Martín D, Caminero E, Barrio R.

PMID: 18367553



Other Laboratory Publications