The Endoplasmic Reticulum Stress Sensor IRE1α Regulates the UV DNA Repair Response through the Control of Intracellular Calcium Homeostasis.
The Endoplasmic Reticulum Stress Sensor IRE1α Regulates the UV DNA Repair Response through the Control of Intracellular Calcium Homeostasis.
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DOI：
10.1016/j.jid.2021.11.010
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发表时间：
2022-06
影响因子：
6.5
通讯作者：
Glick, Adam B.
中科院分区：
文献类型：
--
作者：
Son, Jeongin;Mogre, Saie;Chalmers, Fiona E.;Ibinson, Jack;Worrell, Stephen;Glick, Adam B.
未折叠的蛋白质反应由 UVB 照射激活，但关键介质肌醇需要酶 1a (IRE1α) 的作用尚不清楚。在这里，我们发现表皮 IRE1α 缺失的小鼠对紫外线敏感，细胞凋亡增加，紫外线诱导的环嘧啶二聚体 (CPD) 阳性角质形成细胞快速丧失，以及表皮脱落。在体外，IRE1α缺陷的角质形成细胞增加了UVB敏感性，减少了CPD修复并减少了γH2AX和p-ATR的积累，表明核苷酸切除修复的激活存在缺陷。 XBP1 的敲低或 IRE1α RNase 的药理学抑制并没有表现出 IRE1α 缺陷。紫外线反应的改变与细胞内钙水平和 ROS 升高有关，这是由于内质网钙通道肌醇三磷酸受体 (InsP3R) 失调所致。药理学、遗传学和生化研究将 Ins3PR、细胞内钙和正常 UV DNA 损伤反应对钙和整合素结合蛋白 1 (CIB1) 和 IRE1α-TRAF2-ASK1 复合物的调节联系起来。这些结果表明，IRE1α 激活状态驱动 CIB1 与 InsP3R 或 ASK1 结合，从而调节 UV 后的内质网钙流出、ROS 和 DNA 修复反应。
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.
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