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# Molecular mechanism of the lysosomal transporter PQLC2,a rate-limiting step in cysteamine therapy of cystinosis

Xavier Leray, Christine Anne, Anselm A Zdebik, Bruno Gasnier

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Xavier Leray, Christine Anne, Anselm A Zdebik, Bruno Gasnier. Molecular mechanism of the lysosomal transporter PQLC2,a rate-limiting step in cysteamine therapy of cystinosis. Fourth International Cystinosis Research Symposium, Feb 2014, Irvine, CA, United States. hal-04652928

HAL Id: hal-04652928

https://hal.inrae.fr/hal-04652928v1

Submitted on 18 Jul 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Molecular mechanism of the lysosomal transporter PQLC2, a rate-limiting step in cysteamine therapy of cystinosis

Xavier LERAY¹, Christine ANNE¹, Anselm A. Zdebick² & Bruno Gasnier¹

UNIVERSITÉ
PARIS DESCARTES

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(1) Neurophotonics Laboratory, Université Paris Descartes and Centre National de la Recherche Scientifique (CNRS), Paris, France

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(2) University College London, London, United Kingdom

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Recently, we used proteomics, yeast genetic and transport studies to identify and characterize a lysosomal transporter for cationic amino acids (CAA) termed PQLC2 (Jezegou et al., PNAS 2012). Interestingly, PQLC2 also transports a lysine-like mixed disulfide (MD) that is a chemical intermediate in cysteamine therapy of cystinosis.

In this study, we investigated the transport properties of PQLC2 and explored whether it might represent a therapeutic target to improve cysteamine therapy.

Taken together, our results suggest that PQLC2 mediates a rate-limiting step in lysosomal cystine clearance, that it is expressed at a suboptimal level and is modulated by the electrical potential of the lysosomal membrane. Thus, this study brings forwards novel ways to improve cystine depletion during cysteamine therapy.

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## 1. Strategy to study PQLC2 mechanism

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## 2. PQLC2 transports the mixed-disulfide (MD)

<figure><img src="image_8.png" /><figcaption>B. MD transport current carried by PQLC2</figcaption></figure>

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Jézégou et al., PNAS 2012

## 3. PQLC2 mediates the rate-limiting step in cysteamine therapy

<figure><img src="image_10.png" /><figcaption>B. MD clearance is substantially slower than its synthesis</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>C. Over-expression of PQLC2 in patient fibroblasts increases MD clearance</figcaption></figure>

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## 4. PQLC2 is putatively a uniporter driven solely by lysosomal voltage, suggesting that lysosomal ion channels may modulate the efficiency of cysteamine therapy

<figure><img src="image_13.png" /><figcaption>B. Voltage is the main driving force for CAA transport, despite the strong 2-Unit pH gradient under our experimental conditions</figcaption></figure>

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**Hypothesis**: MD export from lysosomes may be improved by modification of the lysosomal membrane potential by acting on ion channels

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