TXNIP mediates LAT1/SLC7A5 endocytosis to reduce amino acid uptake in cells entering quiescence
Kahlhofer, J.; Marchet, N.; Seifert, B.; Zubak, K.; Hotze, M.; Egger, A.-S.; Manzl, C.; Weyer, Y.; Weys, S.; Offterdinger, M.; Herzog, S.; Reiterer, V.; Kwiatkowski, M.; Wortmann, S. B.; Nemati, S.; Mayr, J. A.; Zschocke, J.; Radlinger, B.; Thedieck, K.; Huber, L. A.; Farhan, H.; de Araujo, M. E.; Kaser, S.; Scholl-Burgi, S.; Karall, D.; Teis, D.
Show abstract
Entry 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 demonstrate that cells entering quiescence select plasma membrane-resident AA transporters for endocytosis and lysosomal degradation, to match AA uptake with reduced translation. We identify the -arrestin TXNIP as a key regulator of AA uptake during quiescence, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) transporter complex in response to reduced AKT signaling. Mechanistically, TXNIP interacts with HECT-type ubiquitin ligases to facilitate transporter ubiquitination. Loss of TXNIP disrupts this regulation, resulting in dysregulated AA uptake, sustained mTORC1 signaling, and accelerated quiescence exit. A novel TXNIP loss-of-function mutation in a patient with severe metabolic disease further supports its role in nutrient homeostasis and human health. These findings highlight TXNIPs role in controlling SLC7A5-SLC3A2 mediated AA acquisition with implications for quiescence biology and disease.
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