MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

Rosa Bartolomeo, Laura Cinque, Chiara De Leonibus, Alison Forrester, Anna Chiara Salzano, Jlenia Monfregola, Emanuela De Gennaro, Edoardo Nusco, Isabella Azario, Carmela Lanzara, Marta Serafini, Beth Levine, Andrea Ballabio, Carmine Settembre

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.

Original languageEnglish (US)
Pages (from-to)3717-3729
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

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Bone Development
Autophagy
Chondrocytes
Phosphatidylinositols
Cartilage
Collagen
Radiation
Bone and Bones
mechanistic target of rapamycin complex 1
Biosynthetic Pathways
Genes
Extracellular Matrix
Phosphotransferases
Phenotype
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bartolomeo, R., Cinque, L., De Leonibus, C., Forrester, A., Salzano, A. C., Monfregola, J., ... Settembre, C. (2017). MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. Journal of Clinical Investigation, 127(10), 3717-3729. https://doi.org/10.1172/JCI94130

MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. / Bartolomeo, Rosa; Cinque, Laura; De Leonibus, Chiara; Forrester, Alison; Salzano, Anna Chiara; Monfregola, Jlenia; De Gennaro, Emanuela; Nusco, Edoardo; Azario, Isabella; Lanzara, Carmela; Serafini, Marta; Levine, Beth; Ballabio, Andrea; Settembre, Carmine.

In: Journal of Clinical Investigation, Vol. 127, No. 10, 02.10.2017, p. 3717-3729.

Research output: Contribution to journalArticle

Bartolomeo, R, Cinque, L, De Leonibus, C, Forrester, A, Salzano, AC, Monfregola, J, De Gennaro, E, Nusco, E, Azario, I, Lanzara, C, Serafini, M, Levine, B, Ballabio, A & Settembre, C 2017, 'MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy', Journal of Clinical Investigation, vol. 127, no. 10, pp. 3717-3729. https://doi.org/10.1172/JCI94130
Bartolomeo R, Cinque L, De Leonibus C, Forrester A, Salzano AC, Monfregola J et al. MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. Journal of Clinical Investigation. 2017 Oct 2;127(10):3717-3729. https://doi.org/10.1172/JCI94130
Bartolomeo, Rosa ; Cinque, Laura ; De Leonibus, Chiara ; Forrester, Alison ; Salzano, Anna Chiara ; Monfregola, Jlenia ; De Gennaro, Emanuela ; Nusco, Edoardo ; Azario, Isabella ; Lanzara, Carmela ; Serafini, Marta ; Levine, Beth ; Ballabio, Andrea ; Settembre, Carmine. / MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 10. pp. 3717-3729.
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