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Molecular signal networks and regulating mechanisms of the unfolded protein response

内质网应激的信号通路以及调控机制

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Abstract

Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1α (IRE1α)). Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-γ (PLCγ)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IRE1α also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca2+ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response.

概 要

文章阐述了内质网应激信号通路及其调控机制; 补充了最新的调控通路; 探讨了内质网应激与肿瘤发生和细胞凋亡的关系。同时将内质网信号通路全面概括到一张图中, 综合阐述了未折叠蛋白反应(UPR)的调控机制, 并把内质网应激与细胞凋亡、肿瘤发生关联到一起, 方便读者更好地了解与学习内质网应激。

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Authors and Affiliations

  1. Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 310036, China

    Xing-zhi Wang, Tao Wang, Jiao-jiao Chen, Hui Hu, Fang Yu, Hui-lin Liu, Xing-yan Jiang & Han-dong Fan

  2. Sichuan Radio and TV University, Chengdu, 610073, China

    Jing Gong

  3. The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China

    Xiao-yuan Xie

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  1. Jing Gong
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Correspondence to Han-dong Fan.

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Project supported by the National Basic Research Program (973) of China (No. 2012CB518900), the National Natural Science Foundation of China (Nos. 31160240 and 31260621), the National Major Scientific and Technological Special Project during the Twelfth Five-year Plan Period of China (No. 2012ZX10002006), the Hangzhou Normal University Supporting Project (No. PE13002004042), and the Natural Science Foundation of Jiangxi Province (No. 20114BAB204016), China

ORCID: Han-dong FAN, http://orcid.org/0000-0001-7040-7744

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Gong, J., Wang, Xz., Wang, T. et al. Molecular signal networks and regulating mechanisms of the unfolded protein response. J. Zhejiang Univ. Sci. B 18, 1–14 (2017). https://doi.org/10.1631/jzus.B1600043

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