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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·2019·Journal of Cell Biology
DOI 10.1083/jcb.201812110PMC PMC6719456
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Abstract

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.

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Crossref · 10.1083/jcb.201812110

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  • The Retromer sub-domain proximity proteome included the RAB7 GAP TBC1D5, the RAB21/RAB32/RAB38 GEF VARP, and the RAB10 GEFs DENND4A and DENND4C.

    “These included known Retromer accessory proteins, the RAB7 GAP TBC1D546,77–81, the RAB21/RAB32/RAB38 GEF VARP (a.k.a. ANKRD27)47,48,82, and the RAB10 GEFs DENND4A and DENND4C83,84.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [78]

  • The knockout phenotype may in part reflect retromer's role as a master regulator of the activity state of endosomal RAB7 through binding to the RAB7 GAP TBC1D5.

    “In part, this phenotype may reflect the role of retromer as a master regulator (Jimenez-Orgaz et al., 2018) of the activity state of endosomal RAB7 through binding to the RAB7 GAP TBC1D5 (Seaman et al., 2009, 2018; Jimenez-Orgaz et al., 2018; Kvainickas et al., 2019).”

    From Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting (2020) · cites this paper as Kvainickas et al., 2019

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Metadata

Authors
Kvainickas, A., Nägele, H., Qi, W., Dokládal, L., Jimenez-Orgaz, A., Stehl, L., Gangurde, D., Zhao, Q., Hu, Z., Dengjel, J., De Virgilio, C., Baumeister, R., & Steinberg, F.
Affiliations
  • Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany 1
  • Faculty of Biology, University of Freiburg, Freiburg, Germany 2
  • Department of Biology, University of Fribourg, Fribourg, Switzerland 3
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2019-08-20
Volume
218
Issue
9
Pages
3019-3038
ISSN
  • 0021-9525
  • 1540-8140
DOI
10.1083/jcb.201812110
PMC
PMC6719456
Cited by
75
References
12
Language
en
Licence
Funders
  • Deutsche Forschungsgemeinschaft (STE 2310/2-1, STE 2310/1-1)
  • Swiss National Science Foundation (31003A-166482/1, 310030_166474/1)
  • European Cooperation in Science and Technology (CA15138)

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