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.

Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer

“…26 Recent work in Hela cells has shown that SLC38A2's adaptive response to nutrient starvation requires retromer-mediated endosomal sorting, which prevents SLC38A2 being sequestered in LAMP1-positive lysosomes. 27 Considering the heterogeneity of response to the stresses, here we assessed the route of SLC38A2 degradation by treating MCF7, MDA-MB-231 and HCC1806 with Bafilomycin A1, a pharmacological inhibitor of autophagosome-lysosome fusion. 28 The levels of SLC38A2 increased consistently after Bafilomycin A1 treatment in all cell lines, suggesting lysosome-mediated degradation of SLC38A2 was also important in these breast cancer cell lines (Fig.…”

Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting

“…In the absence of retromer, RAB7 loses its dynamic organisation on endosomes and lysosomes and becomes hyperactivated and immobile on lysosomes ( Jimenez-Orgaz et al, 2018 ; Seaman et al, 2018 ). 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 ). 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 ).…”

“…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 ). 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 ). 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 ).…”

“…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 ). 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 ). The observed upregulation of CI-MPR, sortilin and cathepsin D expression in H4 neuroglioma cells therefore likely reflects this regulatory role, through a complex compensation in lysosomal function induced by long-term retromer knockout.…”

An update on cellular and molecular determinants of Parkinson's disease with emphasis on the role of the retromer complex

“…Recently, it was shown that the promoter regions of Vps35 and Vps26 have response elements for transcription factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy (Sardiello et al, 2009). Upon nutrient deficiency, autophagy is induced and the expression of Vps35 and Vps26 are upregulated (Curnock, Calcagni, Ballabio, & Cullen, 2019). Another study showed that the pharmacological chaperone R55 stabilizes the retromer complex and diminishes the toxicity of Aß oligomers (Mecozzi et al, 2014) in the Drosophila animal model and in mouse hippocampal neurons.…”