报告题目: Signals from the Lysosome
报告人: Andrea Ballabio, Professor ,Telethon Institute of Genetics and Medicine (TIGEM) and Medical Genetics, Dept. of Pediatrics Federico II Univ. of Naples, Italy; ,Neurological Research Unit, Baylor College of Medicine, Houston, Texas, USA.
报告摘要：
The lysosome plays a major role in cellular clearance. As cellular catabolic needs may vary depending on tissue type, age and environmental conditions, we postulated the presence of a system allowing the coordination of lysosomal activity. Using a systems-biology approach we discovered a gene regulatory network (CLEAR: Coordinated Lysosomal Enhancement And Regulation) that controls lysosomal biogenesis and function and a master gene, the bHLH-leucine zipper transcription factor TFEB, which binds to CLEAR target sites in the promoter of lysosomal genes and positively regulates their expression. TFEB overexpression induces lysosomal biogenesis and promotes cellular clearance (Sardiello et al. Science 2009). We also demonstrated that TFEB is directly involved in the regulation of two important cellular processes that are mediated by the lysosome: autophagy (Settembre et al. Science 2011) and lysosomal exocytosis (Medina et al. Dev. Cell 2011). TFEB overexpression promoted cellular clearance in several murine models of lysosomal storage diseases (LSDs), both in cell culture and in vivo (Medina et al. Dev. Cell 2011). Recent studies in our laboratory revealed that TFEB co-localizes with the master growth regulator kinase mTOR on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTOR, which occurs on the lysosomal surface, inhibits TFEB activity. Conversely, pharmacological inhibition of mTOR, as well as starvation and lysosomal disruption, activate TFEB by promoting its translocation to the nucleus. These data identify an entirely novel, nutrient-sensitive, lysosome-to-nucleus signaling mechanism that senses and regulates the lysosome via mTOR and TFEB (Settembre et al. EMBO J, 2012). In conclusion, we identified a novel, and potentially druggable, mechanism that exerts a global control on cellular clearance and on cellular energy metabolism.
近期文章：
1. Reymond A., Marigo V., Yaylaoglu M.B., Leoni A., Ucla C., Scamuffa N., Caccioppoli C., Dermitzakis E.T., Robert Lyle R., Banfi S., Eichele G., Antonarakis S.E. and Ballabio A. Human chromosome 21 gene expression atlas in the mouse. Nature 420: 582-586.
2. Cosma M.P., Pepe S., Annunziata I., Newbold R.F., Grompe M., Parenti G., Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell 113: 445-456.
3. Settembre C., Annunziata I., Spampanato C., Zarcone D., Cobellis G., Nusco E., Zito E., Tacchetti C., Cosma M.P., Ballabio A. Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency. Proc Natl Acad Sci U S A 104: 4506-4511, 2007.
4. Settembre C., Fraldi A., Jahreiss L., Spampanato C., Venturi C., Medina D., de Pablo R., Tacchetti C., Rubinsztein D.C., Ballabio A. A Block of Autophagy in Lysosomal Storage Disorders. Hum Mol Genet 17: 119-129, 2008.
5. Sardiello M., Palmieri M., di Ronza A., Medina D.L., Valenza M., Gennarino V.A., Di Malta C., Donaudy F., Embrione V., Polishchuk R.S., Banfi S., Parenti G., Cattaneo E and Ballabio A. A Gene Network Regulating Lysosomal Biogenesis and Function. Science 325:473-477.
6. Fraldi A., Annunziata F., Lombardi A., Kaiser H.J., Medina D.L., Spampanato C., Fedele A.O., Polishchuk R., Sorrentino N.C., Simons K., Ballabio A. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO Journal 29:3607-3620.
7. Settembre C., Di Malta C., Polito V.A., Garcia Arencibia M., Vetrini F., Erdin S., Erdin S.U., Huynh T., Medina D.L., Colella P., Sardiello M., Rubinsztein D.C., Ballabio A. TFEB links autophagy to lysosomal biogenesis. Science 332:1429-1433.
8. Medina D.L., Fraldi A., Bouche V., Annunziata F., Mansueto G., Spampanato C., Puri C., Pignata A., Martina J.A., Sardiello M., Palmieri M., Polishchuk R., Puertollano R., Ballabio A. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Developmental Cell 21:421-430.
9. Settembre C., Zoncu R., Medina D.L., Vetrini F., Erdin S., Huynh T., Ferron M., Karsenty G., Vellard M.C., Facchinetti V., Sabatini D., Ballabio A. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO Journal 31:1095-1108.
10. Di Malta C., Fryer J.D., Settembre C., Ballabio A. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proc Natl Acad Sci USA 109(35):E2334-42
时间: 2012年11月13日(星期二), 上午10:00
地点: 遗传发育所1号楼B210报告厅
联系人：杨崇林 （64806596）
