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INFO

SALL & RARE
DESEASES

Spalt-like (SALL) Family of Transcription Factors and rare diseases

Mutations in the Spalt-like (SALL) family of zinc finger transcription factors are associated with various hereditary syndromes, including Townes-Brocks Syndrome (TBS) and Okihiro (Duane-Radial Ray) Syndromes. These syndromes are considered rare diseases and are characterized by symptoms such as hearing loss, renal and limb malformations, among others. We have shown that TBS patient-derived cells have longer and more frequent primary cilia than control cells, leading to errors in the Sonic hedgehog signaling pathway.

Cells derived from Townes-Brocks individuals show longer primary cilia.
Publication: Bozal-Basterra et al. Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome.
The American Journal of Human Genetics (2018), 102, 249–265.
PMID: 29395072

Rare diseases: what are they and who do they affect?

Rare diseases are medical conditions with a prevalence of less than 1 case per 2000 inhabitants. There are estimated to be between 5,000 and 7,000 different rare diseases, and while each one may affect only a small number of individuals worldwide, collectively they impact a significant portion of the global population. It is estimated that between 6 and 8% of the world's population could be affected by one of these rare diseases, resulting in approximately 30 million Europeans suffering from various rare conditions.

In our laboratory, we focus on comprehending the underlying mechanisms of Townes-Brocks Syndrome and other diseases associated with the Ubiquitin-like family, such as Angelman Syndrome.



Spalt-like (SALL) Family of Transcription Factors and Townes-Brocks Syndrome

Our research focuses on understanding the mechanism through which truncations in SALL1 lead to Townes-Brocks Syndrome. By analyzing cells derived from affected patients, we have discovered that primary cilia are longer and more abundant in these cells compared to control cells.

*We express our heartfelt gratitude to the donors and their families who have contributed to this research*.


We study Townes-Brocks Syndrome using both human and mouse cellular models. In Drosophila, we have explored the role of Sall factors in neurodegeneration, limb formation, and nervous system development. Additionally, we have investigated the modification of these proteins by the Small ubiquitin-like modifier (SUMO) and how this modification affects their functions.


If you or a family member are affected by Townes-Brocks Syndrome, please click here.

Related publications
(link to all publications here)

The role of SUMOylation during development

Authors: 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: 2020 Apr 29;48(2):463-478.

PMID: 32311032

Proteostasis and Disease: From Basic Mechanisms to Clinics

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

Advances in Experimental Medicine and Biology

(AEMB, volume 1233), 2020, Springer.

doi: (AEMB, volume 1233), 2020, Springer.

ISBN: 9783030382650

ISBN: 9783030382667

UBIQUITIN-LIKE
PROTEINS

Ubiquitin-like proteins in development and disease

Post-translational modifications (PTMs) mediated by members of the ubiquitin/ubiquitin-like (UbL) family play a vital role in cell survival and the proper functioning of organisms. These modifications involve conserved enzymatic pathways that attach UbLs to other proteins, determining the fate of the target protein. This can lead to changes in its protein-protein interactions, subcellular localization, stability, and degradation. Dysfunctions in these modifications are implicated in various diseases, including cancer, diabetes, neurodegeneration, and rare disorders.

Structural prediction of Ubiquitin and Ubiquitin-Likes

Writing, Editing and Reading the Ubiquitin Code

Regulation of protein homeostasis in diseases

Townes-Brocks Syndrome is caused by mutations in SALL1 that result in a truncated protein, which disrupts cytoplasmic factors and impacts primary cilia. The truncated N-terminal fragment of SALL1 causes changes in the stability of interacting proteins, such as the leucine-zipper protein LUZP1, a negative regulator of ciliogenesis. Our ongoing research aims to study LUZP1 protein homeostasis and whether truncated SALL1 can influence its regulation..



LUZP1 protein localizes to the actin cytoskeleton and the basal body.
Adapted from: Bozal-Basterra et al. LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome.Elife.
2020 Jun 18;9:e55957.
PMID: 32553112

Related publications
(link to all publications here)

Role of SUMOylation in Neurodegenerative Diseases and Inflammation

Editors: 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

Ubiquitin-like molecules in development

UbL molecules are involved in the regulation of development at multiple levels. We study the role of UbLs in the regulation of growth by hormones. 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

Related publications
(link to all publications here)

UBIQUITIN STUDYING
TOOLS

Tools to study ubiquitin-like modifications

We are interested in exploring the role of ubiquitin/ubiquitin-like (UbL) family members during development under normal physiological conditions and their implications in disease processes. However, studying UbL modifications is particularly challenging because they are transient and occur in only a small fraction of the total protein pool. To overcome these challenges, we are actively developing a series of biotin-based strategies to investigate the modifications by UbLs and their subsequent consequences. We also employ other techniques, as TUBEs and SUBEs, and others.

Esquematic representation of biotinylation strageties. Adapted from: A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. Roux KJ, Kim Dl, Raida M, Burke B. J Cell Biol. 2012 Mar 19;196(6):801-10. doi:10.1083/jcb.201112098. Epub 1012 Mar 12. PMID:22412018.

Related publications
(link to all publications here)

BioE3, to identify bona-fide targets of E3 ligases

BioE3 combines BirA specific biotinylation with the BioUbL toolbox. BioE3 attains high specificity and does recognize bona-fide targets of E3 ligases of interest, as oppose to general interactors of those ligases. We proved BioE3 effectiveness with RING and HECT type E3 ligases.

Esquematic representation of BioE3 strategy. Adapted from: BioE3 enables the identification of bona fide targets of E3 ligases. Barroso-Gomila O et al.2023

Related publications
(link to all publications here)

SUMO-ID, to identify interactors of a protein when modified by UbLs

We developed SUMO-ID, a strategy to identify interactors of proteins when modified by UbL molecules by combining fragment complementation with proximity proteomics. We tested the system with well-known modified proteins, such as PML and p53, as well as with less studied proteins, like SALL1. The system exhibits high specificity and has been tested with ubiquitin and SUMO and we expect it to work with other UbLs.

Esquematic representation of the SUMO-ID strategy. Adapted from: Identification of proximal SUMO-dependent interactors using SUMO-ID. Barroso-Gomila O et al. Nat Commun. 2021 Nov 18;12(1):6671. doi:10.1038/s41467-021-26807-6. PMID:34795231.

Related publications
(link to all publications here)

Identification of proximal SUMO-dependent interactors using SUMO-ID

Authors: Barroso-Gomila O, Trulsson F, Muratore V, Canosa I, Merino-Cacho L, Cortazar AR, Pérez C, Azkargorta M, Iloro I, Carracedo A, Aransay AM, Elortza F, Mayor U, Vertegaal ACO, Barrio R*, Sutherland JD*.

Nat Commun.

2021 Nov 18;12(1):6671.

doi: 10.1038/s41467-021-26807-6.

PMID: 34795231

BioUbL, to identify proteins modified by UbLs

BioUbL is a comprehensive toolbox for studying Ubiquitin-like modifications. This toolbox consists of a collection of DNA vectors that facilitate in vivo biotinylation and purification of target proteins. Its flexibility and user-friendly design allow for its application in cell lines, patient-derived cells, and 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

Related publications
(link to all publications here)

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis.

Authors: Mercado-Gómez M, Lopitz-Otsoa F, Azkargorta M, Serrano-Maciá M, Lachiondo-Ortega S, Goikoetxea-Usandizaga N, Rodríguez-Agudo R, Fernández-Ramos D, Bizkarguenaga M, Juan VG, Lectez B, Aloria K, Arizmendi JM, Simon J, Alonso C, Lozano JJ, Avila MA, Banales JM, Marin JJG, Beraza N, Mato JM, Elortza F, Barrio R, Sutherland JD, Mayor U, Martínez-Chantar ML, Delgado TC.

Int J Mol Sci.

2020 Nov 27;21(23):9043.

doi: 10.3390/ijms21239043.

PMID: 33261190

UBIQUITIN RELATED
NETWORKS

Ubiquitin-related Networks

Working in cooperation with other groups makes science to advance faster and is more fun. Along the years, we participated in the following networks in the fields of proteostasis, ubiquitin-like proteins and associated processes.

UbiCode European Training Network To Decipher the Ubiquitin Code

European Trainign Network (H2020, MSCA, EU). UbiCODE: European Research Training to Decipher the Ubiquitin Code. 2018-2021

ProteoCure

COST Action ProteoCure: A sound proteome for a sound body: targeting proteolysis for proteome remodeling. 2021-2025

Interreg POCTEFA ProteoBlood EU

Interreg POCTEFA (EU). Red cooperativa franco-española para el análisis de proteinopatías y el desarrollo de terapias individualizadas en cánceres hematológicos. 2019-2022

UPSclub

UPSClub: Network of local groups with common interests in proteostasis and ubiquitin-like molecules. Ongoing since 2012!

Redes de excelencia UbiRed

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

Proteostasis Cost Eu

COST Action (EU). European network to integrate research on intracellular proteolysis pathways in health and disease. 2014-2018

UPStream European Research Training in the Ubiquitin Proteasome System

European Training Network (FP7, MSCA, EU). European Research Training in the Ubiquitin Proteasome System. 2011-2014