Peer-Reviewed Journal Details
Mandatory Fields
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
March
Molecular Cell
The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling
Published
()
Optional Fields
UNFOLDED PROTEIN RESPONSE ENDOPLASMIC-RETICULUM KINASE CYTOSKELETON DIMERIZATION CALCINEURIN SECRETION CELLS STIM1 STORE
65
885
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.
10.1016/j.molcel.2017.01.020
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