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A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degradation
Journal article   Open access   Peer reviewed

A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degradation

Colette Galet and Mario Ascoli
Molecular endocrinology (Baltimore, Md.), Vol.20(11), pp.2931-2945
11/01/2006
DOI: 10.1210/me.2006-0138
PMID: 16803865
url
https://doi.org/10.1210/me.2006-0138View
Published (Version of record) Open Access

Abstract

Using biochemical and imaging approaches, we examined the postendocytotic fate of the complex formed by human choriogonadotropin (hCG) and a constitutively active mutant of the human lutropin receptor (hLHR-L457R) found in a boy with precocious puberty and Leydig cell hyperplasia. After internalization, some of the complex formed by the hLHR-wild type (hLHR-wt) and hCG recycles to the cell surface, and some is found in lysosomes where the hormone is degraded. In contrast, the complex formed by the hLHR-L457R and hCG is not routed to the lysosomes, most of it is recycled to the cell surface and hormone degradation is barely detectable. For both, hLHR-wt and -L457R, there is an hCG-induced loss of cell surface receptors that accompanies internalization but this loss cannot be prevented by leupeptin. The removal of recycling motifs of the hLHR by truncation of the C-terminal tail at residue 682 greatly enhances the lysosomal accumulation of the hormone-receptor complexes formed by the hLHR-wt or the L457R mutant, the degradation of the internalized hormone, and the loss of cell surface receptors. The degradation of the hormone internalized by these mutants as well as the loss of cell surface receptors is largely prevented by leupeptin. These results highlight a previously unrecognized complexity in the postendocytotic trafficking of the hLHR and document a clear difference between the properties of the constitutively active mutant and the agonist-activated hLHR-wt. This lack of lysosomal degradation of the L457R mutant could contribute to its constitutive activity by prolonging the duration of signaling.
 Amino Acid Substitution Animals Antigens, Surface - metabolism Cells, Cultured Chorionic Gonadotropin - pharmacokinetics Endocytosis - physiology Humans Lysosomes - metabolism Mice Mutant Proteins - metabolism Protein Denaturation Protein Transport Receptors, LH - genetics Receptors, LH - metabolism Transfection

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