TY - JOUR
T1 - MTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy
AU - Bartolomeo, Rosa
AU - Cinque, Laura
AU - De Leonibus, Chiara
AU - Forrester, Alison
AU - Salzano, Anna Chiara
AU - Monfregola, Jlenia
AU - De Gennaro, Emanuela
AU - Nusco, Edoardo
AU - Azario, Isabella
AU - Lanzara, Carmela
AU - Serafini, Marta
AU - Levine, Beth
AU - Ballabio, Andrea
AU - Settembre, Carmine
N1 - Funding Information:
We thank A. Auricchio, G. Napolitano, and G. Diez Roux (from TIGEM) for critical reading of the manuscript; S. Strollo for immunohistochemistry; L. Polishchuk for EM analysis; A. Carissimo for statistical analysis; N. Mizushima, W. Sly (from St. Louis University School of Medicine, St. Louis, USA), and A. Auricchio for sharing the mouse lines used in this work; and D.H. Kim for sharing materials used in this work. This work was supported by grants to CS: Italian Telethon Foundation (TCP12008) and TIGEM institutional Grant, Marie Curie (PCIG13-GA-2013-618805), STAR/Banco di Napoli, Italian Ministry of Research (FIRB RBFR13LH4X), European Research Council starting grant (714551), Penn Orphan Disease Center (MPSI-16-004-01) and National MPS Society; by the NIH U19AI199725 to BL; by the European Research Council Advanced Investigator grant no. 694282 and U.S. National Institutes of Health (R01-NS078072) to AB.
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85030530713&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030530713&partnerID=8YFLogxK
U2 - 10.1172/JCI94130
DO - 10.1172/JCI94130
M3 - Article
C2 - 28872463
AN - SCOPUS:85030530713
SN - 0021-9738
VL - 127
SP - 3717
EP - 3729
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -