Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2
Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2
复制标题
颗粒体蛋白前体是正确 ER 应激反应所必需的，并通过 TNFR2 抑制 ER 应激介导的细胞凋亡。
DOI：
10.1016/j.cellsig.2014.03.026
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发表时间：
2014-07-01
影响因子：
4.8
通讯作者：
Guo, Feng-Jin
中科院分区：
文献类型：
--
作者：
Li, Meiling;Liu, Yanna;Guo, Feng-Jin
颗粒蛋白前体（PGRN）是一种对缺氧和酸中毒有反应的应激反应因子。本研究证明PGRN也是一种内质网应激反应因子：内质网应激诱导PGRN表达，增强其Erk 1/2和Akt信号通路的激活，PGRN缺陷细胞丧失正常的内质网应激反应，PGRN缺陷细胞对内质网应激诱导的细胞凋亡敏感;此外，重组PGRN可以挽救PGRN缺陷细胞中所见的ER应激反应缺陷。机制研究表明，PGRN/TNFR 2对PGRN介导的ER应激反应的调节至关重要：与PGRN类似，在ER应激过程中也诱导TNFR 2的表达，但不诱导TNFR 1的表达;此外，在ER应激后，PGRN与TNFR 2之间的关联显著增强;更重要的是，当TNFR 2信号传导被阻断时，PGRN对ER应激诱导的细胞凋亡的保护作用被取消。此外，TNFR 2细胞外部分中的第二和第三富含半胱氨酸的结构域（CRD 2CRD 3），已知直接结合PGRN，干扰PGRN与TNFR 2的相互作用，并进而消除PGRN介导的Erk 1/2和Akt信号传导的激活和对响应于ER应激的细胞凋亡的保护。总之，PGRN在内质网应激中起重要作用，并通过与TNFR 2相互作用调节内质网应激反应。这项研究为PGRN调节应激反应提供了新的见解，也可能将PGRN作为治疗应激相关疾病的潜在分子靶点。(C)2014 Elsevier Inc. All rights reserved.
Progranulin (PGRN) was reported to be a stress-response factor in response to hypoxia and acidosis. Here we present evidences demonstrating that PGRN is also an endoplasmic reticulum (ER) stress responsive factor: PGRN expression was induced and its activation of Erk1/2 and Akt signaling enhanced in response to ER stress; Normal ER stress response was lost in PGRN deficient cells and PGRN deficient cells became hypersusceptible to ER stress-induced apoptosis; additionally, recombinant PGRN could rescue the defects in ER-stress responses seen in PGRN deficient cells. Mechanistic studies indicated that PGRN/TNFR2 was critical for PGRN mediated regulation of ER stress response: similar to PGRN, the expression of TNFR2, but not TNFR1, was also induced in the course of ER stress; in addition, the association between PGRN and TNFR2 was markedly enhanced following ER stress; More importantly, PGRN protection of ER stress induced apoptosis was abolished when TNFR2 signaling was blocked. In addition, the 2nd and 3rd cysteine-rich domains (CRD) in the extracellular portion of TNFR2 (CRD2CRD3), known to directly bind to PGRN, disturbed the interaction of PGRN with TNFR2, and in turn abolished PGRN-mediated activation of Erk1/2 and Akt signaling and protection against apoptosis in response to ER-stress. Collectively, PGRN plays an important role in ER stress and regulates ER stress response through interacting with TNFR2. This study provides new insight into PGRN regulation of stress response and may also present PGRN as a potential molecular target for treating stress-associated disorders. (C) 2014 Elsevier Inc. All rights reserved.