mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy
Rosa Bartolomeo, … , Andrea Ballabio, Carmine Settembre
Rosa Bartolomeo, … , Andrea Ballabio, Carmine Settembre
Published October 2, 2017; First published September 5, 2017
Citation Information: J Clin Invest. 2017;127(10):3717-3729. https://doi.org/10.1172/JCI94130.
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Concise Communication Bone biology Therapeutics

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

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.

Authors

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

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Figure 7

Proposed pathogenetic mechanism in LSD chondrocytes.

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Proposed pathogenetic mechanism in LSD chondrocytes. Left: In WT chondro...
Left: In WT chondrocytes, collagen homeostasis is reached through equilibrium between the pool that needs to be secreted and the pool that needs to be degraded. Within this context, fine-tuned mTORC1 activity is particularly important for autophagy regulation, autophagosome biogenesis, AV-lysosome fusion, and, in turn, PC2 homeostasis. A key protein complex required for AV-lysosome fusion is represented by Beclin 1–Vps34–UVRAG, a class III–PI3K complex that produces a pool of PI3P required for vesicle fusion. Right: Lysosomal impairment in LSD is responsible for abnormal mTORC1 signaling. Among the autophagy targets of mTORC1, UVRAG activity is particular sensitive to mTORC1 phosphorylation. Thus, in LSD, a stable complex between UVRAG and Rubicon is seen, and insufficient PI3P is produced. This primarily affects AV-lysosome fusion, leading to AV accumulation and a subsequent delay in procollagen trafficking. To overcome the blockage of AV-lysosome fusion and restore proper collagen homeostasis in LSD, therapeutic options can be directed toward either mTORC1 modulation (repression) or pharmacological modulation of the Beclin 1–Vps34 complex (induction).