Group of Ubiquitin Dependent Proteolysis and Intercellular Communication
A research Group with a high level of knowledge and skills in the field of Ubiquitin-dependent proteolysis and Intercellular Communication.
About
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide and represent a major burden for health care systems. To efficiently tackle this group of complex and multifactorial diseases, in their multitude dimensions, a holistic and transversal strategy is required. To boost the existing capacities and competencies, crossing canonical and static boundaries between disciplines, we have implemented a comprehensive and inclusive approach that brings together basic researchers and clinicians, allowing a perspective "from bench to bedside and back again".
The GUIC is devoted to 1) the mechanisms involved in intercellular communication, either direct, between neighbor cells, through gap junctions and tunnelling nanotubes, or at long distances via extracellular vesicles, and 2) the processes required to maintain the quality of cell membrane structures. Furthermore, we aim to elucidate how the disturbance of intercellular crosstalk and failure of membrane quality control systems can contribute to CVD. To address these challenging and ambitious questions, we resort to biochemical techniques, cell-based approaches, animal models of disease and human samples. To successfully and synergistically integrate these approaches, the GUIC encompasses highly motivated people with different scientific and technical backgrounds and interests, who find in our group the favorable environment for creative minds to give free rein to the imagination.
Main achievements
1. Gap junction protein Cx43 exists in extracellular vesicles (EV) where it modulates the sorting of miRNA and facilitates the release of vesicle content into target cells
2. Heart diseases induce gap junctions remodeling and affect EV-mediated communication between cardiac cells, modulating angiogenesis and inflammatory response
3. Cx43 accumulates in the nucleus where it regulates gene transcription
4. Cx43 modulates lysosomal repair and exocytosis
5. Transdermal administration of plant metabolites exert protective effects in pre-clinical models of cardiovascular diseases
Publications
Scientific interests and ongoing research projects
1. Regulation of GJ-mediated intercellular communication in health and disease
Landmark studies from our lab elucidated the mechanisms whereby ubiquitination/ deubiquitination of Cx43 regulates the fate of gap junctions. Furthermore, we unveiled that autophagy degradation of Cx43 can be either ubiquitin-dependent or -independent.
Additionally, we unraveled how the interactome of Cx43 varies in cardiac ischemia and reperfusion. These unbiased studies paved the way to disclose the mechanisms underlying GJ lateralization and autophagy degradation in myocardial infarction.
We are actively working to unveil the association between Cx43 and the oncogenic process.
2. The impact of cell injury in EV secretion
Groundbreaking studies from our group showed for the first time that the GJ protein Cx43 resides at the extracellular vesicles (EV) surface, mediating the release of vesicle content into target cells. Using a comprehensive translational approach, thanks to the long-lasting collaboration with clinicians, we showed that myocardial infarction alters Cx43 secretion in EV. Furthermore, we unraveled that EV secreted by cardiomyocytes under ischemia impacts on endothelial cells, promoting angiogenesis, and on immune cells, affecting their inflammatory profile. Strikingly, we demonstrated that anti-tumor therapies conveyed in Cx43-containing EV are less cardiotoxic.
3. Biomarkers and innovative therapies in pulmonary arterial hypertension (PAH)
We unveiled a new systemic marker of PAH, the miRNA-424; furthermore, we demonstrated that miRNA-424 released by pulmonary endothelial cells targets SMURF-1 in cardiomyocytes and contribute to right ventricle hypertrophy.
We identified a plant-based therapy targeting the right ventricle that ameliorates cardiac hypertrophy. We are now developing innovative drug delivery platforms based on plant vesicles.
4. Non-canonical functions of Cx43
We demonstrated that Cx43 accumulates in the nucleus where it forms functional channels and modulates gene expression. We are now exploring the pathophysiological impact of nuclear Cx43
We showed that upon lysosomal injury Cx43 promotes the repair and exocytosis of lysosomes through the modulation of cortical actin. We are currently investigating the role of Cx43 in lysosomal homeostasis in cardiovascular diseases.