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The ER Stress Sensor IRE1α Regulates the UV DNA Repair Response Through Control of Intracellular Calcium Homeostasis

Son, Jeongin ; Mogre, Saie ; Chalmers, Fiona E. ; Ibinson, Jack ; Worrell, Stephen ; Glick, Adam B.

Journal of investigative dermatology, 2021-11, Vol.142 (6), p.1682-1691.e7 [Periódico revisado por pares]

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  • Título:
    The ER Stress Sensor IRE1α Regulates the UV DNA Repair Response Through Control of Intracellular Calcium Homeostasis
  • Autor: Son, Jeongin ; Mogre, Saie ; Chalmers, Fiona E. ; Ibinson, Jack ; Worrell, Stephen ; Glick, Adam B.
  • É parte de: Journal of investigative dermatology, 2021-11, Vol.142 (6), p.1682-1691.e7
  • Notas: AUTHOR CONTRIBUTIONS
    Conceptualization: AG, JS; Formal analysis: JS; Funding acquisition: AG; Investigation: JS, SM, JI, SW; Project administration: AG; Resources: SM, FC, JS; Supervision: AG; Visualization: JS; Writing-original draft: JS, AG; Writing-review and editing: JS, SM, FC.
  • Descrição: The unfolded protein response is activated by UVB irradiation, but the role of a key mediator, inositol requiring enzyme 1a (IRE1α), is not clear. Here, we show that mice with an epidermal IRE1α deletion are sensitized to UV with increased apoptosis, rapid loss of UV-induced cyclopyrimidine dimer (CPD) positive keratinocytes and sloughing of the epidermis. In vitro , IRE1α deficient keratinocytes have increased UVB sensitivity, reduced CPD repair and reduced accumulation of γH2AX and p-ATR, suggesting defective the activation of nucleotide excision repair. Knockdown of XBP1 or pharmacological inhibition of the IRE1α RNase 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 ER calcium channel inositol triphosphate receptor (InsP3R). Pharmacologic, genetic, and biochemical studies linked regulation of the Ins3PR, intracellular calcium and normal UV DNA damage response to calcium and integrin binding protein 1 (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 ER calcium efflux, ROS and DNA repair responses following UV.
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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