Abstract
Epithelial cells that form the kidney proximal tubule (PT) rely on an intertwined ecosystem of vesicular membrane trafficking pathways to ensure the reabsorption of essential nutrients—a key requisite for homeostasis. The endolysosome stands at the crossroads of this sophisticated network, internalizing molecules through endocytosis, sorting receptors and nutrient transporters, maintaining cellular quality control via autophagy, and toggling the balance between PT differentiation and cell proliferation. Dysregulation of such endolysosome-guided trafficking pathways might thus lead to a generalized dysfunction of PT cells, often causing chronic kidney disease and life-threatening complications. In this review, we highlight the biological functions of endolysosome-residing proteins from the perspectives of understanding—and potentially reversing—the pathophysiology of rare inherited diseases affecting the kidney PT. Using cystinosis as a paradigm of endolysosome disease causing PT dysfunction, we discuss how the endolysosome governs the homeostasis of specialized epithelial cells. This review also provides a critical analysis of the molecular mechanisms through which defects in autophagy pathways can contribute to PT dysfunction, and proposes potential interventions for affected tissues. These insights might ultimately accelerate the discovery and development of new therapeutics, not only for cystinosis, but also for other currently intractable endolysosome-related diseases, eventually transforming our ability to regulate homeostasis and health.
Highlights
Epithelial cells that line the proximal tubule (PT) of the kidney reabsorb a large variety of filtered macromolecules and low-molecular mass-nutrients through a welldeveloped endolysosome system and through membrane trafficking pathways
These paradigms have helped to understand the pathogenesis of common kidney disease entities in which imbalances in the endolysosome system have been implicated in PT dysfunction [7]
Several distincttype complexes containing autophagy-related proteins (ATGs) work with of autophagy, whereby KFERQ-like motif-bearing proteins are recognized by the heatmembrane trafficking regulate a well-oiled, that inshockcomponents cognate proteintoHSPA8/HSC70 and cross the multistep surface of theprocess endolysosome through the binding nucleation to lysosomal-associated membrane protein 2A phagophore (LAMP2A)
Summary
Epithelial cells that line the proximal tubule (PT) of the kidney reabsorb a large variety of filtered macromolecules and low-molecular mass-nutrients through a welldeveloped endolysosome system and through membrane trafficking pathways. Over the last two decades, studies of rare inherited diseases, in combination with advances in technology and high-throughput omics, have provided novel insights into fundamental principles governing the contribution of the endolysosome to the maintenance of homeostasis [5,6]. Through converging approaches, these paradigms have helped to understand the pathogenesis of common kidney disease entities in which imbalances in the endolysosome system have been implicated in PT dysfunction [7]. We highlight potential new, attractive targets for therapeutically tackling cellular adversities linked to cystinosin dysfunction, offering new targetable pathways for this life-threatening disease
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