Cysteinyl leukotriene receptor 1 is a potent regulator of the endosomal‐lysosomal system in the ARPE‐19 retinal pigment epithelial cell line

• Published in: Traffic (Copenhagen, Denmark) Vol. 24; no. 4; pp. 177 - 189
• Main Authors: Koller, Andreas, Brunner, Susanne Maria, Preishuber‐Pflügl, Julia, Runge, Christian, Ladek, Anja‐Maria, Reitsamer, Herbert Anton, Trost, Andrea
• Format: Journal Article
• Language: English
• Published: Former Munksgaard John Wiley & Sons A/S 01.04.2023; Wiley Subscription Services, Inc
• Subjects: Autophagy; Cellular stress response; CysLTR1; EGF endocytosis; Endocytosis; endosomal‐lysosomal system; Endosomes; Endosomes - metabolism; Epithelial Cells; Homeostasis; Internalization; Lysosomes; Lysosomes - metabolism; Organelles; Phagosomes; Retina; retinal pigment epithelial cells; Retinal pigment epithelium; Retinal Pigments - metabolism; Zafirlukast; CysLTR1; retinal pigment epithelial cells; autophagy; EGF endocytosis; endosomal-lysosomal system; Zafirlukast
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12881

The endosomal‐lysosomal system is central for cell homeostasis and comprises the functions and dynamics of particular organelles including endosomes, lysosomes and autophagosomes. In previous studies, we found that the cysteinyl leukotriene receptor 1 (CysLTR1) regulates autophagy in the retinal pigment epithelial cell line ARPE‐19 under basal cellular conditions. However, the underlying mechanism by which CysLTR1 regulates autophagy is unknown. Thus, in the present study, the effects of CysLTR1 inhibition on the endosomal‐lysosomal system are analyzed in detail to identify the role of CysLTR1 in cell homeostasis and autophagy regulation. CysLTR1 inhibition in ARPE‐19 cells by Zafirlukast, a CysLTR1 antagonist, depleted the lysosomal pool. Furthermore, CysLTR1 antagonization reduced endocytic capacity and internalization of epidermal growth factor and decreased levels of the transferrin receptor, CD71. Serum starvation abolished the effect of Zafirlukast on the autophagic flux, which identifies the endocytic regulation of serum components by CysLTR1 as an important autophagy‐modulating mechanism. The role of CysLTR1 in inflammation and cell stress has been exceedingly studied, but its involvement in the endosomal‐lysosomal pathway is largely unknown. This current study provides new insights into basal activity of CysLTR1 on cellular endocytosis and the subsequent impact on downstream processes like autophagy. The current study highlights new insights into how CysLTR1 regulates the autophagic process via the endosomal‐lysosomal pathway. CysLTR1 antagonization induced the autophagy‐related depletion of the lysosomal pool and affected the endocytic capacity (e.g., EGF), which in turn potentially caused a dysregulation of the lysosomal biogenesis. Serum starvation abolished the effect of CysLTR1 inhibition on late endosomes, lysosomes and autophagic flux. Thus, autophagy regulation via CysLTR1 is mainly driven by the endocytic regulation of serum components.