Ca²⁺ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation
Date
2022
Authors
Feliziani, C.
Fernandez, M.
Quassollo, G.
Holstein, D.
Bairo, S.M.
Paton, J.C.
Paton, A.W.
de Batista, J.
Lechleiter, J.D.
Bollo, M.
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Journal article
Citation
Cell Calcium, 2022; 106:102622-1-102622-16
Statement of Responsibility
Constanza Feliziani, Macarena Fernandez, Gonzalo Quassollo, Deborah Holstein, Sebastián M. Bairo, James C. Paton, Adrienne W. Paton, Juan de Batista, James D. Lechleiter, Mariana Bollo
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Abstract
The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed the unfolded protein response (UPR), which attempts to restore ER homoeostasis. If this cannot be done, UPR signalling ultimately induces apoptosis. Ca²⁺ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca²⁺ as an intracellular messenger, the precise mechanism(s) by which Ca²⁺ release affects the UPR remains unknown. Tethering a genetically encoded Ca²⁺ indicator (GCamP6) to the ER membrane revealed novel Ca²⁺ signalling events initiated by Ca²⁺ microdomains in human astrocytes under ER stress, induced by tunicamycin (Tm), an N-glycosylation inhibitor, as well as in a cell model deficient in all three inositol triphosphate receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons and that the Ca²⁺ microdomains impact (PKR)-like-ER kinase (PERK), an UPR sensor, activation. These findings reveal the existence of a Ca²⁺ signal mechanism by which stressor-mediated Ca²⁺ release regulates ER stress.
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