TY - JOUR
T1 - The Endoplasmic Reticulum Stress Sensor IRE1α Regulates the UV DNA Repair Response through the Control of Intracellular Calcium Homeostasis
AU - Son, Jeongin
AU - Mogre, Saie
AU - Chalmers, Fiona E.
AU - Ibinson, Jack
AU - Worrell, Stephen
AU - Glick, Adam B.
N1 - Funding Information:
This work was supported by R01 CA197942 to AG and the United States Department of Agriculture Federal Appropriations Project PEN04607, accession number 1009993. The authors thank the Huck Life Sciences Microscopy and Flow Cytometry cores. The authors acknowledge Laurie Glimcher, Arup Indra, Scott Lindner, and Scott Oakes for providing constructs and mice and Nick Blazanin and Stuart Yuspa for continued support.
Publisher Copyright:
© 2021 The Authors
PY - 2022/6
Y1 - 2022/6
N2 - The unfolded protein response is activated by UVB irradiation, but the role of a key mediator, IRE1α, is not clear. In this study, we show that mice with an epidermal IRE1α deletion are sensitized to UV with increased apoptosis, rapid loss of UV-induced cyclopyrimidine dimer‒positive keratinocytes, and sloughing of the epidermis. In vitro, Ire1α-deficient keratinocytes have increased UVB sensitivity, reduced cyclopyrimidine dimer repair, and reduced accumulation of γH2AX and phosphorylated ATR, suggesting defective activation of nucleotide excision repair. Knockdown of XBP1 or pharmacologic inhibition of the IRE1α ribonuclease did not phenocopy Ire1α deficiency. The altered UV response was linked to elevated intracellular calcium levels and ROS, and this was due to dysregulation of the endoplasmic reticulum calcium channel InsP3R. Pharmacologic, genetic, and biochemical studies linked the regulation of the Ins3PR, intracellular calcium, and normal UV DNA damage response to CIB1 and the IRE1α‒TRAF2‒ASK1 complex. These results suggest a model where IRE1α activation state drives CIB1 binding either to the InsP3R or ASK1 to regulate endoplasmic reticulum calcium efflux, ROS, and DNA repair responses after UV irradiation.
AB - The unfolded protein response is activated by UVB irradiation, but the role of a key mediator, IRE1α, is not clear. In this study, we show that mice with an epidermal IRE1α deletion are sensitized to UV with increased apoptosis, rapid loss of UV-induced cyclopyrimidine dimer‒positive keratinocytes, and sloughing of the epidermis. In vitro, Ire1α-deficient keratinocytes have increased UVB sensitivity, reduced cyclopyrimidine dimer repair, and reduced accumulation of γH2AX and phosphorylated ATR, suggesting defective activation of nucleotide excision repair. Knockdown of XBP1 or pharmacologic inhibition of the IRE1α ribonuclease did not phenocopy Ire1α deficiency. The altered UV response was linked to elevated intracellular calcium levels and ROS, and this was due to dysregulation of the endoplasmic reticulum calcium channel InsP3R. Pharmacologic, genetic, and biochemical studies linked the regulation of the Ins3PR, intracellular calcium, and normal UV DNA damage response to CIB1 and the IRE1α‒TRAF2‒ASK1 complex. These results suggest a model where IRE1α activation state drives CIB1 binding either to the InsP3R or ASK1 to regulate endoplasmic reticulum calcium efflux, ROS, and DNA repair responses after UV irradiation.
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U2 - 10.1016/j.jid.2021.11.010
DO - 10.1016/j.jid.2021.11.010
M3 - Article
C2 - 34808241
AN - SCOPUS:85120955520
VL - 142
SP - 1682-1691.e7
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 6
ER -