mTORC1 Phosphorylates UVRAG to Negatively Regulate Autophagosome and Endosome Maturation

Kim, Young Mi; Jung, Chang Hwa; Seo, Minchul; Kim, Eun Kyoung; Park, Ji‐Man; Bae, Sun Sik; Kim, Do-Hyung

doi:10.1016/j.molcel.2014.11.013

Cited by 233 publications

(188 citation statements)

References 41 publications

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“…Under nutrient-rich conditions, UVRAG is phosphorylated by mechanistic target of rapamcycin complex 1 (mTORC1) (Kim et al, 2015), which enhances the interaction with Rubicon and impairs VPS34 kinase activity, as well as the interaction between UVRAG and the HOPS complex, thus affecting autophagosome maturation. Prevention of UVRAG phosphorylation increases the rate of autophagosome maturation and lysosomal degradation, indicating that mTORC1 not only regulates the induction of autophagy but also facilitates fusion through UVRAG.…”

Section: Rab Proteinsmentioning

confidence: 99%

New insights into autophagosome–lysosome fusion

Nakamura

Yoshimori

2017

Journal of Cell Science

446

324

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Macroautophagy (autophagy) is a highly conserved intracellular degradation system that is essential for homeostasis in eukaryotic cells. Due to the wide variety of the cytoplasmic targets of autophagy, its dysregulation is associated with many diseases in humans, such as neurodegenerative diseases, heart disease and cancer. During autophagy, cytoplasmic materials are sequestered by the autophagosome -a double-membraned structure -and transported to the lysosome for digestion. The specific stages of autophagy are induction, formation of the isolation membrane (phagophore), formation and maturation of the autophagosome and, finally, fusion with a late endosome or lysosome. Although there are significant insights into each of these steps, the mechanisms of autophagosomelysosome fusion are least understood, although there have been several recent advances. In this Commentary, we will summarize the current knowledge regarding autophagosome-lysosome fusion, focusing on mammals, and discuss the remaining questions and future directions of the field.

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Section: Rab Proteinsmentioning

confidence: 99%

New insights into autophagosome–lysosome fusion

Nakamura

Yoshimori

2017

Journal of Cell Science

446

324

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“…In addition, mTORC1 suppresses AV-lysosome fusion via the phosphorylation of UV radiation resistance-associated gene (UVRAG) protein (13). Together with Beclin 1, Vps34, and Vps15, UVRAG forms the endosomal class III-Vps34 complex that catalyzes the production of phosphatidylinositol 3-phosphate (PI3P) required for the fusion of vesicles and (auto)phagosomes with lysosomes (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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

Bartolomeo

Cinque

Leonibus

et al. 2017

Journal of Clinical Investigation

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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

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“…mTOR exists in two large protein complexes: mTOR complex 1 (mTORC1) and 2 (mTORC2), each with unique functions and downstream targets. In particular, mTORC1 integrates various stimuli and signaling networks to coordinate autophagy and cell metabolism (Kim et al 2015). It is well established that cellular autophagy is negatively regulated by mTOR and phosphorylation of mTOR at Ser2448 is an activator of mTORC1 (Yamamoto et al 2014).…”

Section: Introductionmentioning

confidence: 99%

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100 mg/kg body weight/2 days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis. Furthermore, 10 µM Compound C or AMPKα1 siRNA pre-treatment effectively attenuated autophagy and reversed AMPK-mTOR-p70S6K/4EBP1 signaling in NP-treated SCs. Co-treatment with 1 mM AICAR remarkably strengthened NP-induced autophagy and mTOR inhibition in SCs. Together, these data suggest that NP stimulates Sertoli cell autophagy and inhibits mTOR-p70S6K/4EBP1 activity through AMPK activation, which is the potential mechanism responsible for the regulation of testis function and differentiation following NP exposure.

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mTORC1 Phosphorylates UVRAG to Negatively Regulate Autophagosome and Endosome Maturation

Cited by 233 publications

References 41 publications

New insights into autophagosome–lysosome fusion

New insights into autophagosome–lysosome fusion

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

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

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