Vogel, Georg F.;
Ebner, Hannes L.;
de Araujo, Mariana E. G.;
Schmiedinger, Thomas;
Eiter, Oliver;
Pircher, Haymo;
Gutleben, Karin;
Witting, Barbara;
Teis, David;
Huber, Lukas A.;
Hess, Michael W.
Ultrastructural Morphometry Points to a New Role for LAMTOR2 in Regulating the Endo/Lysosomal System
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Media type:
E-Article
Title:
Ultrastructural Morphometry Points to a New Role for LAMTOR2 in Regulating the Endo/Lysosomal System
Contributor:
Vogel, Georg F.;
Ebner, Hannes L.;
de Araujo, Mariana E. G.;
Schmiedinger, Thomas;
Eiter, Oliver;
Pircher, Haymo;
Gutleben, Karin;
Witting, Barbara;
Teis, David;
Huber, Lukas A.;
Hess, Michael W.
Description:
<jats:p>The late endosomal adaptor protein <jats:styled-content style="fixed-case">LAMTOR2</jats:styled-content>/p14 is essential for tissue homeostasis by controlling <jats:styled-content style="fixed-case">MAPK</jats:styled-content> and <jats:styled-content style="fixed-case">mTOR</jats:styled-content> signaling, which in turn regulate cell growth and proliferation, migration and spreading. Moreover, <jats:styled-content style="fixed-case">LAMTOR2</jats:styled-content> 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 <jats:styled-content style="fixed-case">LAMTOR2</jats:styled-content>‐deficient mouse embryonic fibroblasts. Quantitative (immuno‐)electron microscopy of cryo‐fixed samples revealed significantly reduced numbers of recycling tubules emanating from maturing multivesicular bodies (<jats:styled-content style="fixed-case">MVB</jats:styled-content>). Instead, a distinct halo of vesicles surrounded <jats:styled-content style="fixed-case">MVB</jats:styled-content>, tentatively interpreted as detached, jammed recycling tubules. These morphological changes in <jats:styled-content style="fixed-case">LAMTOR2</jats:styled-content>‐deficient cells correlated with the presence of growth factors (e.g. <jats:styled-content style="fixed-case">EGF</jats:styled-content>), but were similarly induced in control cells by inactivating <jats:styled-content style="fixed-case">mTOR</jats:styled-content>. Furthermore, proper transferrin receptor trafficking and recycling were apparently dependent on an intact <jats:styled-content style="fixed-case">LAMTOR</jats:styled-content> complex. Finally, a severe imbalance in the relative proportions of endo/lysosomes was found in <jats:styled-content style="fixed-case">LAMTOR2</jats:styled-content>‐deficient cells, resulting from increased amounts of mature <jats:styled-content style="fixed-case">MVB</jats:styled-content> and (autophago)lysosomes. These observations suggest that the <jats:styled-content style="fixed-case">LAMTOR</jats:styled-content>/Ragulator complex is required not only for maintaining the homeostasis of endo/lysosomal subpopulations but also contributes to the proper formation of <jats:styled-content style="fixed-case">MVB</jats:styled-content>‐recycling tubules, and regulation of membrane/cargo recycling from <jats:styled-content style="fixed-case">MVB</jats:styled-content>.</jats:p><jats:p><jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/tra12271-gra-0001.png" xlink:title="image" /></jats:p>