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M Szaszak, Leibniz Institute of Molecular Pharmacology, Berlin, 13125, Germany
H Chen, National Institutes of Health, Bethesda, United States
H Chen, National Institutes of Health, Bethesda, United States
A Baukal, National Institutes of Health, Bethesda, United States
L Hunyady, Semmelweis University, Budapest, Hungary
K Catt, National Institutes of Health, Bethesda, United States

Correspondence: Marta Szaszak, Email: marta.szaszak{at}gmail.com

Abstract

Little is known about the protein-protein interactions that regulate the trafficking of the angiotensin AT1-receptor (AT1-R) through the biosynthetic pathway. The membrane-proximal region of the cytoplasmic tail of the AT1-R has been identified by site-directed mutagenesis studies as an essential site for normal AT1-R folding and surface expression. Based on yeast two-hybrid screening of a human kidney cDNA library with the AT1-R carboxyl-terminal tail as a bait, we identified the invariant chain (Ii) as a novel interacting protein. This association was confirmed by co-immunoprecipitation and co-localization studies. The binding site for Ii on the AT1-R carboxyl-terminal tail was localized to a site previously identified as important for exit of the AT1-R from the endoplasmic reticulum (ER), and conserved in many G protein-coupled receptors (GPCRs). Transient co-expression of Ii with the AT1-R in CHO-K1 cells consistently reduced the AT1-R density at the cell surface. Furthermore, the interaction of Ii with the carboxyl-terminal tail of the AT1-R caused its retention in the ER and promoted its proteasomal degradation. These observations indicate that Ii and the AT1-R become associated in the early biosynthetic pathway, and that Ii is a negative regulator of AT1-R expression.

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