SNX19 Interacts with Caveolin-1 and Flotillin-1 to Regulate DR Endocytosis and Signaling

Bibhas Amatya, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Jacob Q. Polzin, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Van A. Villar, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Jiang Yang, Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, 20 Penn Street, HSF II, Baltimore, MD 21201, USA.
Prasad Konkalmatt, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Xiaoyan Wang, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Raisha C. Cadme, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Peng Xu, Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
John J. Gildea, Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Santiago Cuevas, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Ines Armando, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Robin A. Felder, Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Pedro A. Jose, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Hewang Lee, Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.

Document Type

Journal Article

Publication Date

2-15-2025

Journal

Biomedicines

Volume

13

Issue

2

DOI

10.3390/biomedicines13020481

Keywords

SNX19; caveolin-1; dopamine D1 receptor; endocytosis; flotillin-1; lipid raft

Abstract

Sorting nexin 19 (SNX19) is important in the localization and trafficking of the dopamine D receptor (DR) to lipid raft microdomains. However, the interaction between SNX19 and the lipid raft components caveolin-1 or flotillin-1 and, in particular, their roles in the cellular endocytosis and cell membrane trafficking of the DR have not been determined. Caveolin-1 and flotillin-1 motifs were analyzed by in silico analysis; colocalization was observed by confocal immunofluorescence microscopy; protein-protein interaction was determined by co-immunoprecipitation. In silico analysis revealed the presence of putative caveolin-1 and flotillin-1 binding motifs within SNX19. In mouse and human renal proximal tubule cells (RPTCs), SNX19 was localized mainly in lipid rafts. In mouse RPTCs transfected with wild-type (WT) Snx19, fenoldopam (FEN), a D-like receptor agonist, increased the colocalization of SNX19 with caveolin-1 and flotillin-1. FEN also increased the co-immunoprecipitation of SNX19 with caveolin-1 and flotillin-1, effects that were prevented by SCH39166, a D-like receptor antagonist. The FEN-mediated increase in the residence of SNX19 in lipid rafts and the colocalization of the DR with caveolin-1 and flotilin-1 were attenuated by the deletion of a caveolin-1 (YHTVNRRYREF) (ΔCav1) or a flotillin-1 (EEGPGTETETGLPVS) (ΔFlot1) binding motif. The FEN-mediated increase in intracellular cAMP production was also impaired by the deletion of either the flotillin-1 or caveolin-1 binding motif. Nocodazole, a microtubule depolymerization inhibitor, interfered with the FEN-mediated increase in the colocalization between SNX19 and DR. SNX19 contains caveolin-1 and flotillin-1 binding motifs, which play an important role in DR endocytosis and signaling.

Department

Medicine

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