Ultrastructural Morphometry Points to a New Role for <scp>LAMTOR2</scp> in Regulating the Endo/Lysosomal System

Vogel, Georg F.; Ebner, Hannes; Araújo, Mariana E. G. de; Schmiedinger, Thomas; Eiter, Oliver; Pircher, Haymo; Gutleben, Karin; Witting, Barbara; Teis, David; Huber, Lukas A.; Hess, Michael W.

doi:10.1111/tra.12271

Cited by 36 publications

(47 citation statements)

References 92 publications

(147 reference statements)

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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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“…HeLa and MEF formed strictly flat, non‐confluent monolayers, CaCo2 grew as confluent, up to ≈20 μm high, polarized monolayers. HPF was performed as previously described in detail …”

Section: Resultsmentioning

confidence: 82%

“…; 5% vol/vol) and methanol (1% vol/vol) gave consistently the best results. As judged from standard 100 nm thin sections the cellular fine structure of these FS‐RH samples appeared generally well preserved (eg, Figures and AB), quite similar to classical FS samples (eg, Reference : Figure ; Ref. : Figures B and 4G).…”

Section: Resultsmentioning

confidence: 94%

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Combining high‐pressure freezing with pre‐embedding immunogold electron microscopy and tomography

Hess

Vogel

Yordanov

et al. 2018

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Immunogold labeling of permeabilized whole-mount cells or thin-sectioned material is widely used for the subcellular localization of biomolecules at the high spatial resolution of electron microscopy (EM). Those approaches are well compatible with either 3-dimensional (3D) reconstruction of organelle morphology and antigen distribution or with rapid cryofixation-but not easily with both at once. We describe here a specimen preparation and labeling protocol for animal cell cultures, which represents a novel blend of specifically adapted versions of established techniques. It combines the virtues of reliably preserved organelle ultrastructure, as trapped by rapid freezing within milliseconds followed by freeze-substitution and specimen rehydration, with the advantages of robust labeling of intracellular constituents in 3D through means of pre-embedding NANOGOLD-silver immunocytochemistry. So obtained thin and semi-thick epoxy resin sections are suitable for transmission EM imaging, as well as tomographic reconstruction and modeling of labeling patterns in the 3D cellular context.

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“…Repeated fusions of endosomes with lysosomes generate endolysosomes with degradation of the intralumenal vesicles harboring internalized receptors (28,(92)(93)(94). The generation of multivesicular endosomes has been implicated in signal transmission, especially for Wnt signaling.…”

Section: Maturation Of Multivesicular Endosomes To Lysosomesmentioning

confidence: 99%

Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Bergeron

Guglielmo

Dahan

et al. 2016

Annu. Rev. Biochem.

105

100

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Epidermal growth factor (EGF) and insulin receptor tyrosine kinases (RTKs) exemplify how receptor location is coupled to signal transduction. Extracellular binding of ligands to these RTKs triggers their concentration into vesicles that bud off from the cell surface to generate intracellular signaling endosomes. On the exposed cytosolic surface of these endosomes, RTK autophosphorylation selects the downstream signaling proteins and lipids to effect growth factor and polypeptide hormone action. This selection is followed by the recruitment of protein tyrosine phosphatases that inactivate the RTKs and deliver them by membrane fusion and fission to late endosomes. Coincidentally, proteinases inside the endosome cleave the EGF and insulin ligands. Subsequent inward budding of the endosomal membrane generates multivesicular endosomes. Fusion with lysosomes then results in RTK degradation and downregulation. Through the spatial positioning of RTKs in target cells for EGF and insulin action, the temporal extent of signaling, attenuation, and downregulation is regulated.

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Ultrastructural Morphometry Points to a New Role for LAMTOR2 in Regulating the Endo/Lysosomal System

Abstract: The late endosomal adaptor protein LAMTOR2/p14 is essential for tissue homeostasis by controlling MAPK and mTOR signaling, which in turn regulate cell growth and proliferation, migration and spreading.

Cited by 36 publications

References 92 publications

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1

Combining high‐pressure freezing with pre‐embedding immunogold electron microscopy and tomography

Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

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