Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid–induced mTORC1 signaling

Kvainickas, Arunas; Nägele, Heike; Qi, Wenjing; Dokládal, Ladislav; Jimenez-Orgaz, Ana; Stehl, Luca; Gangurde, Dipak; Zhao, Qian; Hu, Zehan; Dengjel, Jörn; De Virgilio, Claudio; Baumeister, Ralf; Steinberg, Florian

doi:10.1083/jcb.201812110

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Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid–induced mTORC1 signaling

Kvainickas, Arunas Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany
Nägele, Heike Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany
Qi, Wenjing Faculty of Biology, University of Freiburg, Freiburg, Germany
Dokládal, Ladislav Department of Biology, University of Fribourg, Fribourg, Switzerland
Jimenez-Orgaz, Ana Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany
Stehl, Luca Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany
Gangurde, Dipak Faculty of Biology, University of Freiburg, Freiburg, Germany
Zhao, Qian Faculty of Biology, University of Freiburg, Freiburg, Germany
Hu, Zehan Department of Biology, University of Fribourg, Fribourg, Switzerland
Dengjel, Jörn Department of Biology, University of Fribourg, Fribourg, Switzerland
De Virgilio, Claudio Department of Biology, University of Fribourg, Fribourg, Switzerland
Baumeister, Ralf Faculty of Biology, University of Freiburg, Freiburg, Germany
Steinberg, Florian Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany

02.09.2019

Published in:

The Journal of Cell Biology. - 2019, vol. 218, no. 9, p. 3019–3038

English Retromer is an evolutionarily conserved multiprotein complex that orchestrates the endocytic recycling of integral membrane proteins. Here, we demonstrate that retromer is also required to maintain lysosomal amino acid signaling through mTORC1 across species. Without retromer, amino acids no longer stimulate mTORC1 translocation to the lysosomal membrane, which leads to a loss of mTORC1 activity and increased induction of autophagy. Mechanistically, we show that its effect on mTORC1 activity is not linked to retromer’s role in the recycling of transmembrane proteins. Instead, retromer cooperates with the RAB7-GAP TBC1D5 to restrict late endosomal RAB7 into microdomains that are spatially separated from the amino acid– sensing domains. Upon loss of retromer, RAB7 expands into the ragulator-decorated amino acid–sensing domains and interferes with RAG-GTPase and mTORC1 recruitment. Depletion of retromer in Caenorhabditis elegans reduces mTORC1 signaling and extends the lifespan of the worms, confirming an evolutionarily conserved and unexpected role for retromer in the regulation of mTORC1 activity and longevity.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

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