Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum
- Case Western Reserve University, United States
- University of Victoria, Canada
- Marshall University, United States
Abstract
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: 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 the functional surface expression of GABAA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: HSPA5) and preferentially binds the folded conformation of GABAA 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 GABAA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABAA 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.
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This paper does not report original code. All source data are available in this paper and supplementary information.
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Funding
National Institute of Neurological Disorders and Stroke (R01NS105789)
- Ting-Wei Mu
National Institute of Neurological Disorders and Stroke (R01NS117176)
- Ting-Wei Mu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This animal study (Protocol #: 2018-0017) was approved by the Institutional Animal Care and Use Committees (IACUC) at Case Western Reserve University and was carried out in agreement with the recommendation of the American Veterinary Medical Association Panel on Euthanasia. Animals were maintained in groups. The ARRIVE guidelines have been followed.
Copyright
© 2024, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum
eLife 13:e84798.
https://doi.org/10.7554/eLife.84798
