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
ITN (EU) 2011-2014
