The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes

Takahashi, Yusuke; Nada, Shigeyuki; Mori, Shunsuke; Soma-Nagae, Taeko; Oneyama, Chitose; Okada, Masato

doi:10.1016/j.bbrc.2011.12.082

Cited by 46 publications

(54 citation statements)

References 20 publications

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“…It is unclear how the assembly of BORC is regulated within the cell or if this complex regulates mTORC1, but the authors imply that Ragulator interacts with BORC subunits (Pu et al, 2015), which would indicate a role for the c17orf59-Ragulator complex in lysosomal positioning as a part of BORC. This is consistent with literature that Ragulator components are important for maintaining endolysosomal morphology and biogenesis (Teis et al, 2006; Nada et al, 2009; Takahashi et al, 2012; Vogel et al, 2015) and consistent with our observed alterations in lysosomal staining in cells that overexpress c17orf59 (Figure 4E and Figure 5B). It is possible that Ragulator binds to c17orf59 and BORC in a Rag- and mTORC1-independent manner to control endosome and lysosome morphology.…”

Section: Discussionsupporting

confidence: 93%

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

et al. 2015

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SUMMARY mTORC1 controls key processes that regulate cell growth, including mRNA translation, ribosome biogenesis and autophagy. Environmental amino acids activate mTORC1 by promoting its recruitment to the cytosolic surface of the lysosome, where its kinase is activated downstream of growth factor signaling. mTORC1 is brought to the lysosome by the Rag GTPases, which are tethered to the lysosomal membrane by Ragulator, a lysosome-bound scaffold. Here, we identify c17orf59 as a Ragulator-interacting protein that regulates mTORC1 activity through its interaction with Ragulator at the lysosome. The binding of c17orf59 to Ragulator prevents Ragulator interaction with the Rag GTPases, both in cells and in vitro, and decreases Rag GTPase lysosomal localization. Disruption of the Rag-Ragulator interaction by c17orf59 impairs mTORC1 activation by amino acids by preventing mTOR from reaching the lysosome. By disrupting the Rag-Ragulator interaction to inhibit mTORC1, c17orf59 expression may represent another mechanism to modulate nutrient sensing by mTORC1.

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Section: Discussionsupporting

confidence: 93%

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

et al. 2015

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“…Rab7 staining was more punctate in GCase deficient cells, and appeared to have a greater perinuclear localisation. The co-localisation between Rab7 and cathepsin D in Gba1 KO and HET cells was increased compared to Gba1 WT cells ( Gba1 KO 161% ± 22.66; Gba1 HET 126% ± 11.04) (Figure 3B) suggesting slower lysosomal maturation/recycling (25,28). Increased cholesterol is a marker of immature/dysfunctional lysosomes (28).…”

Section: Resultsmentioning

confidence: 98%

Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease

et al. 2016

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Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD.

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“…Recent studies show that the LAMTOR1-p14-MP1 complex is essential for regulating the activity of the mammalian Target Of Rapamycin Complex 1 (mTORC1) on lysosomes [26]. Conditional ablation of LAMTOR1 in mouse epidermis suggests that the LAMTOR1 related complex is involved in promoting lysosome-mediated degradation of cellular components, and is also required for regulating the formation of autolysosome [27].…”

Section: Discussionmentioning

confidence: 99%

Identification of host proteins interacting with the integrin-like A domain of Toxoplasma gondii micronemal protein MIC2 by yeast-two-hybrid screening

Wang

Fang

Yuan

et al. 2014

Parasites & Vectors

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Background: Toxoplasma gondii is an obligate intracellular protozoan, causing the important zoonosis toxoplasmosis. This parasite utilizes a unique form of locomotion called gliding motility to find and invade host cells. The micronemal adhesin MIC2 plays critical roles in these processes by binding to substrates and host cell receptors using its extracellular adhesive domains. Although MIC2 is known to mediate important interactions between parasites and host cells during invasion, the specific host proteins interacting with MIC2 have not been clearly identified. In this study, we used a yeast-two-hybrid system to search for host proteins that interact with MIC2.

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The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes

Cited by 46 publications

References 20 publications

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease

Identification of host proteins interacting with the integrin-like A domain of Toxoplasma gondii micronemal protein MIC2 by yeast-two-hybrid screening

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