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TFEB controls retromer expression in response to nutrient availability
Abstract
Endosomal recycling maintains the cell surface abundance of nutrient transporters for nutrient uptake, but how the cell integrates nutrient availability with recycling is less well understood. Here, in studying the recycling of human glutamine transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), SNAT1 (SLC38A1), and SNAT2 (SLC38A2), we establish that following amino acid restriction, the adaptive delivery of SNAT2 to the cell surface relies on retromer, a master conductor of endosomal recycling. Upon complete amino acid starvation or selective glutamine depletion, we establish that retromer expression is upregulated by transcription factor EB (TFEB) and other members of the MiTF/TFE family of transcription factors through association with CLEAR elements in the promoters of the retromer genes VPS35 and VPS26A. TFEB regulation of retromer expression therefore supports adaptive nutrient acquisition through endosomal recycling.
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Previous work did not find a change in surface recycling of SLC7A5 in VPS35 knockout HeLa cells.
“Previous work also did not find a change in surface recycling of another binding partner of SLC3A2, SLC7A5 (LAT1, system L), in VPS35 knockout HeLa cells, and at the sensitivity of western blotting we did not identify a change in surface SLC3A2 levels with VPS35 suppression (Figure 5C), indicating that additional regulatory mechanisms likely contribute to SNX3-Retromer mediated recycling of SLC3A2”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [120]
In Results and discussion, “Retromer regulates endosomal recycling of glutamine transporters” (page unavailable), the paper reports that LAT1 (SLC7A5) whole-cell levels and degradation kinetics were unaffected in VPS35-knockout HeLa cells, and concludes that retromer promotes recycling of ASCT2 and SNAT2, but not LAT1. It does not report a direct measurement of LAT1 surface recycling in those cells; its statement about unchanged LAT1 cell-surface levels concerns amino-acid withdrawal, not a recycling assay. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAdditional regulatory mechanisms likely contribute to SNX3-Retromer mediated recycling of SLC3A2 heterodimers.
“indicating that additional regulatory mechanisms likely contribute to SNX3-Retromer mediated recycling of SLC3A2 heterodimers [120].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [120]
Loss of retromer leads to impaired mTORC1 activity, induction of autophagy, and the appearance of swollen and evenly dispersed lysosomes.
“This leads to impaired mTORC1 activity and the induction of autophagy, and the appearance of swollen and evenly dispersed lysosomes (Jimenez-Orgaz et al., 2018; Cui et al., 2019; Curnock et al., 2019; 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 Curnock et al., 2019
Retromer-knockout cells display activation of the TFEB transcription factors, which are master regulators of cellular nutrient sensing and energy metabolism.
“Moreover, retromer-knockout cells display activation of the TFEB transcription factors (Curnock et al., 2019), master regulators of cellular nutrient sensing and energy metabolism (Sardiello et al., 2009; Settembre et al., 2011).”
From Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting (2020) · cites this paper as Curnock et al., 2019
Besides its role in cargo retrieval and recycling within the endosomal pathway, retromer has emerged as a master regulator of RAB7 in nutrient sensing and signalling.
“Thus, besides its role in cargo retrieval and recycling within the endosomal pathway (Steinberg et al., 2013), retromer has emerged as a master regulator of RAB7 in nutrient sensing and signalling (Jimenez-Orgaz et al., 2018; Curnock et al., 2019; 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 Curnock et al., 2019
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Citations
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Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting
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Self-citationJones, E., Adams, H., Chen, K.-E., Maroof, F., Ibbotson, T. M., Nakamura, Y., Banks, P. J., Healy, M. D., Lewis, P. A., Heesom, K. J., et al. (2026) · doi:10.64898/2026.05.14.724903
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Metadata
- Authors
- Curnock, R., Calcagni, A., Ballabio, A., & Cullen, P. J.
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2019-11-06
- Volume
- 218
- Issue
- 12
- Pages
- 3954-3966
- ISSN
- 0021-9525
- 1540-8140
- PMC
- PMC6891082
- Cited by
- 32
- References
- 4
- Language
- en
- Funders
- Medical Research Council (MR/L007363/1, MR/P018807/1)
- Wellcome Trust (104568/Z/14/2)
- Italian Telethon Foundation (TGM16CB6)
- European Research Council (694282)
- National Institutes of Health (R01-NS078072)
- Associazione Italiana per la Ricerca sul Cancro (IG2018 22103)
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