A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome

Mark J. Henderson; Kathleen A. Trychta; Shyh Ming Yang; Susanne Bäck; Adam Yasgar; Emily S. Wires; Carina Danchik; Xiaokang Yan; Hideaki Yano; Lei Shi; Kuo Jen Wu; Amy Q. Wang; Dingyin Tao; Gergely Zahoránszky-Kőhalmi; Xin Hu; Xin Xu; David Maloney; Alexey V. Zakharov; Ganesha Rai; Fumihiko Urano; Mikko Airavaara; Oksana Gavrilova; Ajit Jadhav; Yun Wang; Anton Simeonov; Brandon K. Harvey

doi:10.1016/j.celrep.2021.109040

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome

Mark J. Henderson, Kathleen A. Trychta, Shyh Ming Yang, Susanne Bäck, Adam Yasgar, Emily S. Wires, Carina Danchik, Xiaokang Yan, Hideaki Yano, Lei Shi, Kuo Jen Wu, Amy Q. Wang, Dingyin Tao, Gergely Zahoránszky-Kőhalmi, Xin Hu, Xin Xu, David Maloney, Alexey V. Zakharov, Ganesha Rai, Fumihiko UranoMikko Airavaara, Oksana Gavrilova, Ajit Jadhav, Yun Wang, Anton Simeonov, Brandon K. Harvey

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.

Original language	English
Article number	109040
Journal	Cell Reports
Volume	35
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2021.109040
State	Published - Apr 27 2021

Keywords

ER calcium
ER proteome
ER retention sequence
ER stress
SERCaMP
bromocriptine
diabetes
endoplasmic reticulum
exodosis
stroke

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10.1016/j.celrep.2021.109040

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Henderson, M. J., Trychta, K. A., Yang, S. M., Bäck, S., Yasgar, A., Wires, E. S., Danchik, C., Yan, X., Yano, H., Shi, L., Wu, K. J., Wang, A. Q., Tao, D., Zahoránszky-Kőhalmi, G., Hu, X., Xu, X., Maloney, D., Zakharov, A. V., Rai, G., ... Harvey, B. K. (2021). A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome. Cell Reports, 35(4), Article 109040. https://doi.org/10.1016/j.celrep.2021.109040

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title = "A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome",

abstract = "Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.",

keywords = "ER calcium, ER proteome, ER retention sequence, ER stress, SERCaMP, bromocriptine, diabetes, endoplasmic reticulum, exodosis, stroke",

author = "Henderson, {Mark J.} and Trychta, {Kathleen A.} and Yang, {Shyh Ming} and Susanne B{\"a}ck and Adam Yasgar and Wires, {Emily S.} and Carina Danchik and Xiaokang Yan and Hideaki Yano and Lei Shi and Wu, {Kuo Jen} and Wang, {Amy Q.} and Dingyin Tao and Gergely Zahor{\'a}nszky-K{\H o}halmi and Xin Hu and Xin Xu and David Maloney and Zakharov, {Alexey V.} and Ganesha Rai and Fumihiko Urano and Mikko Airavaara and Oksana Gavrilova and Ajit Jadhav and Yun Wang and Anton Simeonov and Harvey, {Brandon K.}",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = apr,

day = "27",

doi = "10.1016/j.celrep.2021.109040",

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Henderson, MJ, Trychta, KA, Yang, SM, Bäck, S, Yasgar, A, Wires, ES, Danchik, C, Yan, X, Yano, H, Shi, L, Wu, KJ, Wang, AQ, Tao, D, Zahoránszky-Kőhalmi, G, Hu, X, Xu, X, Maloney, D, Zakharov, AV, Rai, G, Urano, F, Airavaara, M, Gavrilova, O, Jadhav, A, Wang, Y, Simeonov, A & Harvey, BK 2021, 'A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome', Cell Reports, vol. 35, no. 4, 109040. https://doi.org/10.1016/j.celrep.2021.109040

TY - JOUR

T1 - A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome

AU - Henderson, Mark J.

AU - Trychta, Kathleen A.

AU - Yang, Shyh Ming

AU - Bäck, Susanne

AU - Yasgar, Adam

AU - Wires, Emily S.

AU - Danchik, Carina

AU - Yan, Xiaokang

AU - Yano, Hideaki

AU - Shi, Lei

AU - Wu, Kuo Jen

AU - Wang, Amy Q.

AU - Tao, Dingyin

AU - Zahoránszky-Kőhalmi, Gergely

AU - Hu, Xin

AU - Xu, Xin

AU - Maloney, David

AU - Zakharov, Alexey V.

AU - Rai, Ganesha

AU - Urano, Fumihiko

AU - Airavaara, Mikko

AU - Gavrilova, Oksana

AU - Jadhav, Ajit

AU - Wang, Yun

AU - Simeonov, Anton

AU - Harvey, Brandon K.

PY - 2021/4/27

Y1 - 2021/4/27

N2 - Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.

AB - Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.

KW - ER calcium

KW - ER proteome

KW - ER retention sequence

KW - ER stress

KW - SERCaMP

KW - bromocriptine

KW - diabetes

KW - endoplasmic reticulum

KW - exodosis

KW - stroke

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U2 - 10.1016/j.celrep.2021.109040

DO - 10.1016/j.celrep.2021.109040

M3 - Article

C2 - 33910017

AN - SCOPUS:85105062521

SN - 2639-1856

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 109040

ER -

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome

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