ABSTRACT
Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurodegenerative, neurological, and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is not well understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric type A (GABAA) receptors. Here, we show that Hsp47 enhances neuronal GABAA receptor functional surface expression, acting after Binding immunoglobulin Protein (BiP) to preferentially bind the folded conformation of GABAA receptors. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. These Hsp47 properties are also extended to other Cys-loop receptors, including nicotinic acetylcholine receptors. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 also plays a critical and general role in the maturation of multi-subunit neuroreceptors.
Highlights
Hsp47 positively regulates the functional surface expression of endogenous GABAA receptors.
Hsp47 acts after BiP and preferentially binds the folded conformation of GABAA receptors.
Hsp47 promotes the subunit-subunit assembly of GABAA receptors.
Hsp47 plays a critical and general role in the maturation of multi-subunit neuroreceptors.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵4 These authors contributed equally to this work.
Abstract updated for clarity; Figure 6A updated to include individual data points; Supplemental file updated: new Figure S3 included for clarity, and Figure S4 (original Figure S3) updated to include individual data points. References 65 and 67 combined due to redundancy.
