Area 5: Cellular and molecular immunology “MOLECULAR MECHANISMS INVOLVED IN ATTENUATING FcεRI EXPRESSION AND SIGNALING” Rossella Paolini Associate Professor of immunology Department of Molecular Medicine Phone/Fax: 0039‐06‐4468448 E‐mail: [email protected] Abstract In addition to being major effector cells in the elicitation of allergic response, mast cells play a significant role in host defense against invading parasites. Indeed, mast cells can produce, store and release a broad spectrum of pro‐inflammatory mediators and deliver exosomes throughout the body after activation by several stimuli, being the ligation of the high affinity receptor for IgE (FcεRI) the most efficient and the best characterized. FcεRI belongs to a multisubunit immunoreceptor family characterized by the presence of subunits, distinct for each receptor, used for ligand binding and others that share conserved cytoplasmic motifs responsible for cell activation. The receptor complex lacks intrinsic enzymatic activity but transduces intracellular signals through association with cytoplasmic protein tyrosine kinases. Regulation of the signals generated as a consequence of antigen interaction with specific IgE bound to FcεRI, causes a shift in the resting state equilibrium of phosphorylation and dephosphorylation that serves to maintain homeostasis. The outcome of this activated state is the release of preformed mediators and the de novo synthesis of eicosanoids, cytokines and chemokines that result in both immediate and late‐phase reactions. The complex and highly regulated apparatus leading to mast cell activation is counterbalanced by an equally sophisticated series of inhibitory mechanisms. Notably, a negative‐feedback regulation of FcεRI‐mediated signals is provided by the internalization and delivery of activated receptor complexes to lysosomes for degradation, mainly occurring via clathrin‐dependent endocytosis. More recently, the implication of a lipid raft‐
dependent FcεRI ubiquitination in controlling the endocytosis of activated receptors has been also envisaged. In such context, the outcome of our proposal would be to characterize in depth the molecular mechanisms that ensure a proper delivery of internalized FcεRI complexes to lysosomes for degradation, thus providing a negative‐feedback regulation of receptor activity and mast cell functions. 1
GROUP COMPONENTS This research project will be performed in the Laboratory of Immunology, Department of Molecular Medicine, “Sapienza” University of Rome. Rosa Molfetta Research Associate Linda Quatrini PhD Student Cristina Capuano Post doctoral fellow Relevant publications 1. Molfetta R, Gasparrini F, Peruzzi G, Vian L, Piccoli M, Frati L, Santoni A, Paolini R. (2009). Lipid raft‐dependent FcεRI ubiquitination regulates receptor endocytosis through the action of ubiquitin binding adaptors. PLoS One. 4(5):e5604. doi: 10.1371/journal.pone.0005604. Epub 2009 May 19. 2. Molfetta R, Gasparrini F, Santoni A, Paolini R. (2010). Negative regulation of FcεRI‐
mediated basophil activation by the Cbl family of adaptor proteins. In: Basophil Granulocytes (Editor: Paul K. Vellis). Nova Science Publishers, Hauppauge, USA. 3. Porzia A, Lanzardo S, Citti A, Cavallo F, Forni G, Santoni A, Galandrini R, Paolini R. (2010). Attenuation of PI3K/Akt‐Mediated Tumorigenic Signals through PTEN Activation by DNA Vaccine‐Induced Anti‐ErbB2 Antibodies. J Immunol. Apr 15;184(8):4170‐7. doi: 10.4049/jimmunol.0903375. Epub 2010 Mar 10. 4. Molfetta R, Gasparrini F, Santoni A, Paolini R. (2010). Ubiquitination and endocytosis of the high affinity receptor for IgE. Mol Immunol. Sep;47(15):2427‐34. doi: 10.1016/j.molimm.2010.06.003. Epub 2010 Jul 16. Review.
5. Gasparrini F, Molfetta R, Santoni A, Paolini R. (2011). Cbl Family Proteins: Balancing FcεRI‐
Mediated Mast Cell and Basophil Activation. Int Arch Allergy Immunol. 156(1):16-26. doi:
10.1159/000322236. Epub 2011 Mar 29. Review. 6. Capuano C, Paolini R, Molfetta R, Frati L, Santoni A, Galandrini R. (2012). PIP2‐dependent regulation of Munc13‐4 endocytic recycling: impact on the cytolytic secretory pathway. Blood. Mar 8;119(10):2252‐62. doi: 10.1182/blood‐2010‐12‐324160. Epub 2012 Jan 23. 7. Gasparrini F, Molfetta R, Quatrini L, Frati L, Santoni A, Paolini R. (2012). Syk‐dependent regulation of Hrs hosphryaltion and ubiquitination upon FcεRI‐engagement: impact on Hrs membrane/cytosol localization. Eur J Immunol. Oct;42(10):2744‐53. doi: 10.1002/eji.201142278. Epub 2012 Jul 25. 2