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Carmine Settembre

Assistant Investigator, TIGEM

Assistant Telethon Scientist (DTI), Telethon Foundation, Italy

Role of lysosomal processes in skeletal development and diseases, and identification of therapeutic approaches for the treatment of skeletal manifestation in Lysosomal Storage Disorders.

The lysosome is the "recycling center" of each cell, breaking down unwanted material into simple products for the cell to use to build new material. Lysosomes rely on the action of various enzymes to carry out the stepwise degradation of the substrates.  In recent years, however, the lysosome has emerged as a key signaling centre, participating in the relays with signaling molecules. These observations suggest that lysosomes hold a novel, yet unexplored, role in the regulation of fundamental developmental processes.

Skeletal development is a coordinated process that in humans begins during embryogenesis and terminates at puberty. Skeletal elements are composed of two distinct tissues, cartilage and bone, and by three distinct cell types, chondrocytes, osteoblasts and osteoclasts. Several human genetic disorders are associated with defective skeletogenesis. Clinical studies indicate that 10% of all genes associated with skeletal disorders encode  lysosomal proteins. The resulting disorders are known as lysosomal storage sisorders (LSDs) whose incidence is about 1 in 5,000 - 10,000 births.  Despite this, the mechanisms by which lysosomal dysfunction affects skeletal development and function are still unknown, and the efficacy of current therapies on the skeletal system are limited.

The goal of this lab group is to characterize the consequences of lysosomal dysfunction on major signaling pathways involved in skeletogenesis and to identify tools and pathways that prevent accumulation and/or promote clearance of storage in bone cells. We propose an unbiased approach to identify the differential responses of wild type and LSD cells to the molecules that regulate skeletogenesis.  In addition, we plan to identify which factors secreted during skeletogenesis regulate lysosomal and autophagic functions. Finally, in vivo mouse models and pharmacological approaches can be used to test how modulating selected signaling pathways can be exploited to treat skeletal defects caused by lysosomal dysfunction.

Cinque L, Forrester A, Bartolomeo R, Svelto M, Venditti R, Montefusco S, Polishchuk E, Nusco E, Rossi A, Medina DL, Polishchuk R, De Matteis MA, Settembre C (2015). FGF signalling regulates bone growth through autophagy. Nature 528(7581):272-5. doi10.1038/nature16063.

Settembre C, De Cegli R, Mansueto G, Saha P, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch T, Wollenberg A, Di Bernardo D, Chan L, Irazoqui J, Ballabio A (2013). TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nature Cell Biology. 15(6):647-58. doi: 10.1038/ncb2718. 

Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A (2012). A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31(5):1095-108. doi: 10.1038/emboj.2012.32. 

Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (2011). TFEB links autophagy to lysosomal biogenesis. Science. 332(6036):1429-33. doi: 10.1126/science.1204592.

Settembre C, Arteaga-Solis E, McKee MD, de Pablo R, Al Awqati Q, Ballabio A, Karsenty G (2008). Proteoglycan desulfation determines the efficiency of chondrocyte autophagy and the extent of FGF signaling during endochondral ossification. Genes Dev. 22(19):2645-50. doi: 10.1101/gad.1711308.

Carmine Settembre PhD

Cell Biology and Disease Mechanisms

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