TXNIP mediates LAT1/SLC7A5 endocytosis to limit amino acid uptake in cells entering quiescence
Entry into and exit from cellular quiescence require dynamic adjustments in nutrient acquisition, yet the mechanisms by which quiescent cells downregulate amino acid (AA) transport remain poorly understood. Here we show that cells entering quiescence selectively target plasma membrane-resident amino acid transporters for endocytosis and lysosomal degradation. This process matches amino acid uptake with reduced translational demand and promotes survival during extended periods of quiescence. Mechanistically, we identify the α-arrestin TXNIP as a key regulator of this metabolic adaptation, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) AA transporter complex in response to reduced AKT signaling. To promote transporter ubiquitination, TXNIP interacts with NEDD4L and other HECT-type ubiquitin ligases. Loss of TXNIP disrupts this regulation, resulting in dysregulated amino acid uptake, sustained mTORC1 signaling, and ultimately cell death under prolonged quiescence. The characterization of a novel TXNIP loss-of-function variant in a patient with a severe metabolic disease further supports its role in nutrient homeostasis and human health. Together, these findings highlight TXNIP's central role in controlling nutrient acquisition and metabolic plasticity with implications for quiescence biology and diseases.
Authors
- David Teis (ORCID: https://orcid.org/0000-0002-8181-0253)
- Veronika Reiterer (ORCID: https://orcid.org/0000-0002-7734-1255)
- S H Nemati (ORCID: https://orcid.org/0000-0002-6909-9614)
- Chiara Volani (ORCID: https://orcid.org/0000-0003-3600-4735)
- Sebastian Herzog (ORCID: https://orcid.org/0000-0001-7167-3489)
- Saskia Brigitte Wortmann (ORCID: https://orcid.org/0000-0002-1968-8103)
- Bettina Sarg (ORCID: https://orcid.org/0000-0002-4785-8739)
- Sabine Weys
- Martin Offterdinger (ORCID: https://orcid.org/0000-0003-3396-7042)
- Lukas Alfons Huber (ORCID: https://orcid.org/0000-0003-1116-2120)
- Claudia Manzl (ORCID: https://orcid.org/0000-0001-6269-7585)
- Daniela Karall (ORCID: https://orcid.org/0000-0002-4846-1047)
- Kathrin Thedieck (ORCID: https://orcid.org/0000-0002-9069-2930)
- Hesso Farhan (ORCID: https://orcid.org/0000-0002-0889-8463)
- Anna-Sophia Egger (ORCID: https://orcid.org/0000-0002-5204-7121)
- Yannick Weyer (ORCID: https://orcid.org/0000-0002-2612-6774)
- Mariana E. G. de Araújo (ORCID: https://orcid.org/0000-0003-0576-2680)
- Leopold Kremser
- Johannes Zschocke (ORCID: https://orcid.org/0000-0002-0046-8274)
- Bernhard Radlinger (ORCID: https://orcid.org/0000-0002-7034-8155)
- Susanne Kaser (ORCID: https://orcid.org/0000-0003-2524-5218)
- B. Seifert
- Johannes A. Mayr (ORCID: https://orcid.org/0000-0001-6970-336X)
- Jennifer Kahlhofer (ORCID: https://orcid.org/0000-0002-7686-9488)
- Madlen Hotze (ORCID: https://orcid.org/0009-0001-1816-2089)
- Marcel Kwiatkowski (ORCID: https://orcid.org/0000-0002-5804-6031)
- Lucija Kucej
- Sabine Scholl-Bürgi
- Nikolas Marchet
- Kristian Zubak
Institutions
- University Medical Center Groningen (NL)
- Innsbruck Medical University (AT)
- Institute of Science and Technology Austria (AT)
- University of Freiburg (DE)
- University of Groningen (NL)
- German Cancer Research Center (DE)
- Universität Innsbruck (AT)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Ruhrlandklinik (DE)
- Amalia Kinderziekenhuis (NL)
- Essen University Hospital (DE)
- Gesundheit Österreich (AT)
- Salzburger Landeskliniken (AT)
- Altonaer Kinderkrankenhaus (DE)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1038/s44318-025-00608-9
- Citations
- 1
- Primary Topic
- Amino Acid Enzymes and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.11