Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum

• Published in: eLife 2024-07, Vol.13
• Main Authors: Wang, Ya-Juan, Di, Xiao-Jing, Zhang, Pei-Pei, Chen, Xi, Williams, Marnie P, Han, Dong-Yun, Nashmi, Raad, Henderson, Brandon J, Moss, Fraser J, Mu, Ting-Wei
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); Animals; Antibodies; assembly; Biochemistry and Chemical Biology; Biosynthesis; Cell Biology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Chaperone BiP - metabolism; Epilepsy; folding; GABA; GABAA receptors; GRP78 protein; Heat shock proteins; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Homeostasis; Hsp47; Humans; Localization; Membrane proteins; Metabolic disorders; Molecular modelling; Neurons - metabolism; Potassium; Protein deficiency; Protein folding; Protein structure; Proteins; Proteomics; proteostasis; Rats; Receptor mechanisms; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Scientific equipment and supplies industry; T cell receptors; γ-Aminobutyric acid; γ-Aminobutyric acid A receptors
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.84798

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is poorly understood. Previous proteomics studies identified Hsp47 (Gene: ), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric acid type A (GABA ) receptors. Here, we show that Hsp47 enhances the functional surface expression of GABA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: ) and preferentially binds the folded conformation of GABA receptors without inducing the unfolded protein response in HEK293T cells. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABA receptor variants in HEK293T cells. Hsp47 also promotes the surface trafficking of other Cys-loop receptors, including nicotinic acetylcholine receptors and serotonin type 3 receptors in HEK293T cells. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 plays a critical and general role in the maturation of multi-subunit Cys-loop neuroreceptors.