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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/48858

Title: Functional studies of the SLE-Risk Genes BANK1 and BLK in B-cell Pathways
Authors: Díaz Barreiro, Alejandro
Direction: Alarcón Riquelme, Marta Eugenia
Collaborator: Universidad de Granada. Programa Oficial de Doctorado en Biomedicina
Universidad de Granada. Centro Pfizer. Genómica e Investigación Oncológica (GENYO)
Issue Date: 2017
Submitted Date: 20-Oct-2017
Abstract: Systemic lupus erythematosus (SLE) is a multisystemic and chronic disorder considered as the prototype autoimmune disease. It is characterized by the production of autoantibodies against nuclear self-antigens. Subsequent deposition of immune complexes in end-organs such as kidneys, joints or skin causes inflammation and tissue damage. The factors that lead to the onset of SLE are several and of different nature. The disease develops when environmental factors, such as infections or ultraviolet light, affect individuals genetically predisposed to encourage the breakdown of tolerance to ubiquitous self-antigens. In this sense, the study of the genetic basis of lupus has been of enormous importance to describe the processes that underlie its pathophysiology. B lymphocyte kinase (BLK) and the B-cell scaffold protein with ankyrin repeats BANK1 are two examples of genes consistently associated with SLE through GWAS. In addition, both proteins show an expression almost restricted to B lymphocytes and have been shown to act together upon B cell receptor (BCR) signaling. In 2012 our group identified a rare variant associated with lupus in the BLK gene. A substitution of an alanine for a threonine at position 71 (A71T), within the SH3 domain of the protein, generated a kinase with increased susceptibility to degradation. In order to describe in depth the effects of this non-synonymous variant over BLK homeostasis and function, we have compared mRNA expression, protein degradation, ubiquitination, subcellular localization and traffic toghetehr with coinmunoprecipitation experiments. The variant increases the in vitro ubiquitination of the kinase and degradation rate in B cells. In addition, it enhances the overall threonine- and tyrosine-phosphorylation of the protein. We hypothesize this is caused by the disruption of an intramolecular interaction between the SH3 domain and the linker segment that joins the kinase and SH2 domains of BLK, which has been shown to regulate the activity of this type of kinases. In addition, it has been described that BLK is ubiquitinated after its activation as a signal for degradation, which supports our hypothesis. On the other hand, the A71T substitution also affects the interaction of BLK with BANK1 by significantly reducing it. In contrast, neither an effect on localization nor subcellular trafficking were observed. Low levels of BLK have been repeatedly proposed as a risk factor in the development of SLE. The effect of variant A71T, in this sense, would represent an additive risk effect. BANK1 contains a putative TIR domain sequence. Our group has intensively investigated its involvement in the Toll-like receptor pathway. Taken together, these data implicate BANK1 in the TLR pathway and suggest its role as a signaling enhancer mediated through the interaction with MyD88 and TRAF6, particularly by promoting TRAF6 Lys-63-linked ubiquitination. The description of pathological pathways such as those studied in this work together with other findings achieved daily in the world's laboratories will allow the development of new personalized and effective therapies for SLE.
Sponsorship: Tesis Univ. Granada. Programa Oficial de Doctorado en Biomedicina
Publisher: Universidad de Granada
Keywords: Lupus eritematoso
Genética
Inmunología
Proteínas quinasas
Marcadores bioquímicos
Ubicuitina
UDC: 61
575
575.113
576.36
320102
URI: http://hdl.handle.net/10481/48858
ISBN: 9788491637103
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Díaz Barreiro, A. Functional studies of the SLE-Risk Genes BANK1 and BLK in B-cell Pathways. Granada: Universidad de Granada, 2017. [http://hdl.handle.net/10481/48858]
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