Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation

FELIZIANI, CONSTANZA; HOLSTEIN, DEBORAH; PATON, ADRIENNE W; BOLLO, MARIANA; FERNANDEZ, MACARENA; BAIRO, SEBASTIÁN M; DE BATISTA, JUAN; QUASSOLLO, GONZALO; PATON, JAMES C; LECHLEITER, JAMES D

CELL CALCIUM.

CHURCHILL LIVINGSTONE

Año: 2022 vol. 106

0143-4160

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.