CE11 - Caractérisation des structures et relations structure-fonctions des macromolécules biologiques

Dynamics of lysosomal amino acid transporters – LYSOTRANS

Dynamics of lysosomal amino acid transporters

In addition to their metabolic role in degrading and recycling cell components, lysosomes act as signaling hubs to coordinate cell responses. Lysosomal nutrient transporters participate in these responses, but they remain understudied due to technical difficulties. Our project focuses on one of them.

General aim

Our consortium aims at characterizing a lysosomal transporter involved in nutrient recycling and nutrient sensing using biochemical and biophysical approaches.

Our approaches combine proteoliposome studies of the purified protein with in-cell techniques of a mutant protein misrouted to the plasma membrane.

This work is in progress.

This project should help understand the mechanisms underlying the metabolic and signaling roles of lysosomes in health and disease.

Functional Study of Lysosomal Nutrient Transporters, Xavier Leray, Corinne Sagné, Bruno Gasnier, in Ion and Molecule Transport in Lysosomes, (2020), Gasnier, B. (Ed.), Zhu, M.X. (Ed.), CRC Press, doi.org/10.1201/b22460

Gasnier B. (2021) Plug-and-socket mechanisms in nutrient sensing by lysosomal amino acid transporters. Proc. Natl. Acad. Sci. USA 118, e2102173118; doi.org/10.1073/pnas.2102173118

Leray C, Conti R, Li Y, Debacker C, Castelli F, Fenaille F, Zdebik AA, Pusch M, Gasnier B. Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism, Proc Natl Acad Sci U S A. 118, e2025315118; doi.org/10.1073/pnas.2025315118

Lysosomes are well-known degradative organelles involved in the maintenance of cells and tissues. Interestingly, recent research has shown that they have wider cellular functions, including their role as signaling hubs for the master growth regulator mTOR. Lysosomal amino acid transporters may modulate mTOR complexes recruited to the lysosomal surface by controlling intra-lysosomal levels of amino acids sensed by this protein kinase, especially arginine. Our consortium of three laboratories (Paris, Saclay and Stanford) aims to characterize the lysosomal transporter for cationic amino acids, PQLC2, and, for some aspects, a paralogous cystine transporter, cystinosin. We will use biochemical, biophysical and structural studies of purified proteins, and electrophysiological analysis of the transport-associated currents to analyze their functional properties and the underlying mechanisms. The resulting knowledge and tools will be used to examine the contribution of PQLC2 to intra-lysosomal arginine sensing and mTORC1 signaling. Our proposal will thus provide new knowledge on an under-characterized family of amino acid transporters implicated in a human disease, cystinosis, and in a fast-developing area of cell biology. As mTOR dysregulation is associated with a wide set of diseases ranging from cancer, obesity and type 2 diabetes to neurodegeneration, our proposal has broad relevance to human health.

Project coordinator

Monsieur Bruno Gasnier (Neurophotonique)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Neurophotonique
I2BC Institut de Biologie Intégrative de la Cellule

Help of the ANR 518,246 euros
Beginning and duration of the scientific project: October 2018 - 36 Months

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