Leray, X; Conti, R; Li, Y; Debacker, C; Castelli, F; Fenaille, F; Zdebik, AA; ... Gasnier, B; + view all Leray, X; Conti, R; Li, Y; Debacker, C; Castelli, F; Fenaille, F; Zdebik, AA; Pusch, M; Gasnier, B; - view fewer (2021) Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism. Proceedings of the National Academy of Sciences , 118 (32) , Article e2025315118. 10.1073/pnas.2025315118.

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Abstract

Lysosomes degrade and recycle cell components and integrate environmental and intracellular cues to regulate cell growth, metabolism, and autophagy. The lysosomal transporter PQLC2 exports cationic amino acids from lysosomes, and under amino acid starvation, it recruits to lysosomes a signaling complex implicated in neurological diseases. In this study, we show that PQLC2 transport activity is uncoupled from the lysosomal pH gradient and other ion gradients and that it is selectively modulated by arginine through a trans-inhibition mechanism. Kinetic modeling suggests that arginine accelerates the closing of its cytosolic gate. We propose a signaling model in which PQLC2 transduces the nutrient status to its cognate complex through opposing effects of lysosomal membrane potential and cytosolic arginine on its conformational state.

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