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Traffic. 2015 Jun;16(6):617-34. doi: 10.1111/tra.12271. Epub 2015 Apr 14.

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

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Division of Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, A-6020, Innsbruck, Austria.
Division of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80-82, A-6020, Innsbruck, Austria.
Current address: Department for Trauma Surgery, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria.
Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, A-6020, Innsbruck, Austria.


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. Moreover, LAMTOR2 critically controls architecture and function of the endocytic system, including epidermal growth factor receptor (EGFR) degradation in lysosomes, positioning of late endosomes and defense against intracellular pathogens. Here we describe the multifaceted ultrastructural phenotype of the endo/lysosomal system of LAMTOR2-deficient mouse embryonic fibroblasts. Quantitative (immuno-)electron microscopy of cryo-fixed samples revealed significantly reduced numbers of recycling tubules emanating from maturing multivesicular bodies (MVB). Instead, a distinct halo of vesicles surrounded MVB, tentatively interpreted as detached, jammed recycling tubules. These morphological changes in LAMTOR2-deficient cells correlated with the presence of growth factors (e.g. EGF), but were similarly induced in control cells by inactivating mTOR. Furthermore, proper transferrin receptor trafficking and recycling were apparently dependent on an intact LAMTOR complex. Finally, a severe imbalance in the relative proportions of endo/lysosomes was found in LAMTOR2-deficient cells, resulting from increased amounts of mature MVB and (autophago)lysosomes. These observations suggest that the LAMTOR/Ragulator complex is required not only for maintaining the homeostasis of endo/lysosomal subpopulations but also contributes to the proper formation of MVB-recycling tubules, and regulation of membrane/cargo recycling from MVB.


LAMTOR; MAPK; MVB; Ragulator; electron tomography; endosome; high-pressure freezing; immuno-gold; mTOR; p14

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