Autophagy captures the retromer-TBC1D5 complex to inhibit receptor recycling
Date
2024
Authors
Carosi, J.M.
Hein, L.K.
Sandow, J.J.
Dang, L.V.P.
Hattersley, K.
Denton, D.
Kumar, S.
Sargeant, T.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Autophagy, 2024; 20(4):863-882
Statement of Responsibility
Julian M. Carosi, Leanne K. Hein, Jarrod J. Sandow, Linh V. P. Dang, Kathryn Hattersley, Donna Denton, Sharad Kumar and Timothy J. Sargeant
Conference Name
Abstract
Retromer prevents the destruction of numerous receptors by recycling them from endosomes to the trans-Golgi network or plasma membrane. This enables retromer to fine-tune the activity of many signaling pathways in parallel. However, the mechanism(s) by which retromer function adapts to environmental fluctuations such as nutrient withdrawal and how this affects the fate of its cargoes remains incompletely understood. Here, we reveal that macroautophagy/autophagy inhibition by MTORC1 controls the abundance of retromer+ endosomes under nutrient-replete conditions. Autophagy activation by chemical inhibition of MTOR or nutrient withdrawal does not affect retromer assembly or its interaction with the RAB7 GAP protein TBC1D5, but rather targets these endosomes for bulk destruction following their capture by phagophores. This process appears to be distinct from amphisome formation. TBC1D5 and its ability to bind to retromer, but not its C-terminal LC3-interacting region (LIR) or nutrient-regulated dephosphorylation, is critical for retromer to be captured by autophagosomes following MTOR inhibition. Consequently, endosomal recycling of its cargoes to the plasma membrane and trans-Golgi network is impaired, leading to their lysosomal turnover. These findings demonstrate a mechanistic link connecting nutrient abundance to receptor homeostasis.
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Dissertation Note
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Description
Published online: 17 Nov 2023
Data source: Supplemental data, https://doi.org/10.1080/15548627.2023.2281126
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