mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy
mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy
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DOI：
10.1172/jci94130
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发表时间：
2017-10-02
影响因子：
15.9
通讯作者：
Settembre, Carmine
中科院分区：
文献类型：
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作者：
Bartolomeo, Rosa;Cinque, Laura;Settembre, Carmine
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）激酶通过激活生物合成途径和抑制分解代谢途径，特别是大自噬途径促进细胞生长。mTORC 1活化的先决条件是其易位到溶酶体表面。mTORC 1的失调与几种疾病的发病机制有关，但其在骨骼疾病中的作用在很大程度上是未知的。在这里，我们表明，增强mTORC 1信号阻滞骨生长在溶酶体胆积症（LSD）。我们发现，溶酶体功能障碍诱导组成性溶酶体协会和随后的激活mTORC 1的软骨细胞，细胞致力于骨延长。mTORC 1使蛋白质UV辐射抗性相关基因（UVRAG）过度磷酸化，降低相关Beclin 1-Vps 34复合物的活性，从而抑制磷酸肌醇产生。限制磷酸肌醇的产生导致LSD软骨细胞自噬通量的阻断。因此，LSD软骨细胞不能适当地分泌胶原蛋白，胶原蛋白是软骨细胞外基质的主要成分。在LSD小鼠模型中，mTORC 1信号传导的正常化或Beclin 1-Vps 34-UVRAG复合物的刺激挽救了自噬通量，恢复了软骨中的胶原蛋白水平，并改善了骨表型。总之，这些数据揭示了mTORC 1和自噬在骨骼疾病发病机制中的作用，并提出了治疗LSD的潜在治疗方法。
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.