The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling

Alexander R. van Vliet; Francesca Giordano; Sarah Gerlo; Inmaculada Segura; Sofie Van Eygen; Geert Molenberghs; Susana Rocha; Audrey Houcine; Rita Derua; Tom Verfaillie; Jeroen Vangindertael; Herlinde De Keersmaecker; Etienne Waelkens; Jan Tavernier; Johan Hofkens; Wim Annaert; Peter Carmeliet; Afshin Samali; Hideaki Mizuno; Patrizia Agostinis

doi:10.1016/j.molcel.2017.01.020

The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling

Alexander R. van Vliet, Francesca Giordano, Sarah Gerlo, Inmaculada Segura, Sofie Van Eygen, Geert Molenberghs, Susana Rocha, Audrey Houcine, Rita Derua, Tom Verfaillie, Jeroen Vangindertael, Herlinde De Keersmaecker, Etienne Waelkens, Jan Tavernier, Johan Hofkens, Wim Annaert, Peter Carmeliet, Afshin Samali, Hideaki Mizuno, Patrizia Agostinis

Cellular & Molecular Medicine

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

193 Citations (Scopus)

Abstract

Loss of ER Ca²⁺ homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca²⁺. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca²⁺ fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca²⁺ store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca²⁺ elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton.

Original language	English
Pages (from-to)	885-899.e6
Journal	Molecular Cell
Volume	65
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2017.01.020
Publication status	Published - 2 Mar 2017

Keywords

ER-PM contact sites
FLNA
PERK
SOCE
STIM1
actin cytoskeleton
actin relocalization
calcium signaling
endoplasmic reticulum
extended-Synaptotagmin 1
plasma membrane
unfolded protein response

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10.1016/j.molcel.2017.01.020

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van Vliet, A. R., Giordano, F., Gerlo, S., Segura, I., Van Eygen, S., Molenberghs, G., Rocha, S., Houcine, A., Derua, R., Verfaillie, T., Vangindertael, J., De Keersmaecker, H., Waelkens, E., Tavernier, J., Hofkens, J., Annaert, W., Carmeliet, P., Samali, A., Mizuno, H., & Agostinis, P. (2017). The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling. Molecular Cell, 65(5), 885-899.e6. https://doi.org/10.1016/j.molcel.2017.01.020

@article{5d160ed27fd84da2a6e38de8ca7319c8,

title = "The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling",

abstract = "Loss of ER Ca2+ homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca2+. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca2+ fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca2+ store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca2+ elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton.",

keywords = "ER-PM contact sites, FLNA, PERK, SOCE, STIM1, actin cytoskeleton, actin relocalization, calcium signaling, endoplasmic reticulum, extended-Synaptotagmin 1, plasma membrane, unfolded protein response",

author = "\{van Vliet\}, \{Alexander R.\} and Francesca Giordano and Sarah Gerlo and Inmaculada Segura and \{Van Eygen\}, Sofie and Geert Molenberghs and Susana Rocha and Audrey Houcine and Rita Derua and Tom Verfaillie and Jeroen Vangindertael and \{De Keersmaecker\}, Herlinde and Etienne Waelkens and Jan Tavernier and Johan Hofkens and Wim Annaert and Peter Carmeliet and Afshin Samali and Hideaki Mizuno and Patrizia Agostinis",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = mar,

day = "2",

doi = "10.1016/j.molcel.2017.01.020",

language = "English",

volume = "65",

pages = "885--899.e6",

journal = "Molecular Cell",

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van Vliet, AR, Giordano, F, Gerlo, S, Segura, I, Van Eygen, S, Molenberghs, G, Rocha, S, Houcine, A, Derua, R, Verfaillie, T, Vangindertael, J, De Keersmaecker, H, Waelkens, E, Tavernier, J, Hofkens, J, Annaert, W, Carmeliet, P, Samali, A, Mizuno, H & Agostinis, P 2017, 'The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling', Molecular Cell, vol. 65, no. 5, pp. 885-899.e6. https://doi.org/10.1016/j.molcel.2017.01.020

TY - JOUR

T1 - The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling

AU - van Vliet, Alexander R.

AU - Giordano, Francesca

AU - Gerlo, Sarah

AU - Segura, Inmaculada

AU - Van Eygen, Sofie

AU - Molenberghs, Geert

AU - Rocha, Susana

AU - Houcine, Audrey

AU - Derua, Rita

AU - Verfaillie, Tom

AU - Vangindertael, Jeroen

AU - De Keersmaecker, Herlinde

AU - Waelkens, Etienne

AU - Tavernier, Jan

AU - Hofkens, Johan

AU - Annaert, Wim

AU - Carmeliet, Peter

AU - Samali, Afshin

AU - Mizuno, Hideaki

AU - Agostinis, Patrizia

PY - 2017/3/2

Y1 - 2017/3/2

N2 - Loss of ER Ca2+ homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca2+. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca2+ fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca2+ store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca2+ elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton.

AB - Loss of ER Ca2+ homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca2+. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca2+ fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca2+ store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca2+ elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton.

KW - ER-PM contact sites

KW - FLNA

KW - PERK

KW - SOCE

KW - STIM1

KW - actin cytoskeleton

KW - actin relocalization

KW - calcium signaling

KW - endoplasmic reticulum

KW - extended-Synaptotagmin 1

KW - plasma membrane

KW - unfolded protein response

UR - https://www.scopus.com/pages/publications/85013498608

U2 - 10.1016/j.molcel.2017.01.020

DO - 10.1016/j.molcel.2017.01.020

M3 - Article

SN - 1097-2765

VL - 65

SP - 885-899.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling

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Keywords

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