Data di Pubblicazione:
2013
Citazione:
SPHINGOLIPIDS AS SIGNALING MOLECULES: THEIR INVOLVEMENT IN HEALTH AND DISEASE / E. Chiricozzi ; docente guida: S. Sonnino ; coordinatore: F. Bonomi. DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2013 Feb 19. 25. ciclo, Anno Accademico 2012. [10.13130/chiricozzi-elena_phd2013-02-19].
Abstract:
Sphingolipids (SLs) are minor cell membrane amphyphilic components, residing in the external layer of the plasma membrane (PM), with the hydrophobic moiety, the ceramide (Cer), inserted into the membrane layer and the hydrophilic head group protruding toward the extracellular environment. They are a family of several compounds with different structural properties: the phospholipid, sphingomyelin (SM), the glycosphingolipids (GSLs) characterized for containing a complex oligosaccharide chain as hydrophilic moiety and gangliosides, GSLs containing sialic acid. As membrane components, SLs participate to modulate several cell processes, such as cell growth, differentiation, morphogenesis, cell to matrix interaction and cell to cell communication. From this, it follows that a defect in SL metabolism can obviously lead to a great number of dysfunctions, ranging from neurodegeneration to cancer.
Along my Ph.D. course I considered the different faces of SLs roles: from their involvement in physiology to that in pathology.
i.SPHINGOLIPIDS and HEALT.
SLs cluster to form SL-enriched domains on cellular PM (lipid rafts, caveolae, and glycosynapses) providing a microenvironment within the PM for reciprocal interaction between lipids and proteins. In particular biochemical analyses have demonstrated that GSLs-enriched microdomains contain several transducer molecules, especially membrane-anchored signal transduction molecules, such as tyrosine kinases belonging to the Src family. Although it has been speculated that GSLs are involved in cell differentiation, proliferation and functions such as phagocytosing, there are quite few evidence that GSLs, by themselves, directly mediate signal transduction, which lead to these cell functions.
LACTOSYLCERAMIDE-ENRICHED MICRODOMAIN in NEUTROPHILIS. Lactosylceramide (LacCer), a neutral GSL, is abundantly expressed on human neutrophils, and specifically recognizes several pathogenic microorganisms. It has been previously demonstrated that LacCer forms PM lipid domains, that can be separated by detergent treatment of cells followed by ultracentrifugation, and that these lipid domains are coupled with Lyn, a Src family kinase. Ligand binding to LacCer activates Lyn, resulting in neutrophils functions, such as superoxide generation, phagocytosis and migration. The presence of LacCer molecular species with Cer containing a very long fatty acid chain is necessary for the association of Lyn with LacCer-enriched PM domains and LacCer-mediated functions. Lyn is associated by a palmitoyl anchor to the cytoplasmic leaflet, while LacCer is inserted into the outer layer of membrane bilayer. So the question is: how does LacCer interact with signal transducer molecules?
The GSL-protein interactions in neutrophilis have been investigated by photoactivable GSLs. These molecules have been administered and taken up by the cell PM. When cells are illuminated, the photoactivable group, linked to the terminal portion of Cer, yields a very reactive intermediate, that covalently binds the molecules in the close environment.
For the first time, at the best of our knowledge, we show a direct connection, across the PM, between GSLs and palmitoylated proteins: these results suggest that LacCer with a long fatty acid chain in Cer moiety could be the key-player of the transduction of information across the PM, modulating membrane interdigitation, through the long acyl chain, and forming specific PM microdomains.
ii. SPHINGOLIPIDS and DISEASES. IMPLICATION IN NEURODEGENERATIVE DISORDERS. SLs are particularly abundant in the nervous system where they play crucial roles regulating signaling events. Severe neurodegeneration is the prominent pathological hallmark of the most sphingolipidoses, inherited metabol
Tipologia IRIS:
Tesi di dottorato
Keywords:
sphingolipids
Elenco autori:
E. Chiricozzi
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