Intracellular Protein Degradation and Rare Diseases
We are a Cell Biology laboratory mainly interested in two research areas: i) the regulation of the major intracellular protein degradation mechanisms (autophagy and the ubiquitin-proteasome system), and ii) the relevance of their alterations in various rare diseases.
Autophagy and the ubiquitin-proteasome system,especially the former, can be induced or inhibited by several environmental components, such as growth factors, nutrients and hormones. This occurs through a complex signalling network, which is still poorly understood. Since both mechanisms play essential roles in cellular homeostasis and control many important cell processes, defects in their functions have been associated to several human pathologies. Therefore, a detailed knowledge of these signalling networks may allow the identification of new targets for their diagnosis and treatment.
Rare diseases are life-threatening or chronically debilitating diseases with low prevalence (with European standards, less than one patient in 2,000 people). They include about 5,000-7,000 different diseases and this explains that although individually they have a low prevalence, they all affect, approximately, 6-8% of the population. Moreover, these diseases could also serve as models to understand more prevalent pathologies. In the work that we perform within this context, we collaborate with other groups of the Spanish public consortium "Centre for Biomedical Network Research on Rare Diseases (CIBERER)" to analyze, first, possible alterations in autophagy and/or the ubiquitin-proteasome system in those rare diseases in which undegraded proteins, polysaccharides or lipids accumulate within the cells, and, second, the consequences of restoring the normal function of these mechanisms in those rare diseases where they are altered.
Oxidative stress regulates the ubiquitin-proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy.
Launay N, Ruiz M, Fourcade S, Schlüter A, Guilera C, Ferrer I, Knecht E, Pujol A
Brain : a journal of neurology , 2013 Mar, vol. 136, pag. 891-904
Glucose induces autophagy under starvation conditions by a p38 MAPK-dependent pathway.
Moruno-Manchón JF, Pérez-Jiménez E, Knecht E
The Biochemical journal , 2013 Jan 15, vol. 449, pag. 497-506
PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity.
Errafiy R, Aguado C, Ghislat G, Esteve JM, Gil A, Loutfi M, Knecht E
PloS one , 2013, vol. 8, pag. e83318
Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-ß (CaMKK-ß).
Ghislat G, Patron M, Rizzuto R, Knecht E
The Journal of biological chemistry , 2012 Nov 9, vol. 287, pag. 38625-36, Impact Factor: 4.651
Annexin A5 stimulates autophagy and inhibits endocytosis.
Ghislat G, Aguado C, Knecht E
Journal of cell science , 2012 Jan 1, vol. 125, pag. 92-107, Impact Factor: 5.877