Full Text:  <1052>

Summary:  <345>

CLC number: Q257

On-line Access: 2017-01-03

Received: 2016-03-15

Revision Accepted: 2016-07-18

Crosschecked: 2016-12-12

Cited: 0

Clicked: 1200

Citations:  Bibtex RefMan EndNote GB/T7714


Han-dong Fan


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2017 Vol.18 No.1 P.1-14


Molecular signal networks and regulating mechanisms of the unfolded protein response

Author(s):  Jing Gong, Xing-zhi Wang, Tao Wang, Jiao-jiao Chen, Xiao-yuan Xie, Hui Hu, Fang Yu, Hui-lin Liu, Xing-yan Jiang, Han-dong Fan

Affiliation(s):  Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China; more

Corresponding email(s):   fanhandong@whu.edu.cn

Key Words:  Unfolded protein response, Endoplasmic reticulum (ER) stress, Mechanism, Signal networks, Homeostasis

Share this article to: More |Next Article >>>

Jing Gong, Xing-zhi Wang, Tao Wang, Jiao-jiao Chen, Xiao-yuan Xie, Hui Hu, Fang Yu, Hui-lin Liu, Xing-yan Jiang, Han-dong Fan. Molecular signal networks and regulating mechanisms of the unfolded protein response[J]. Journal of Zhejiang University Science B, 2017, 18(1): 1-14.

@article{title="Molecular signal networks and regulating mechanisms of the unfolded protein response",
author="Jing Gong, Xing-zhi Wang, Tao Wang, Jiao-jiao Chen, Xiao-yuan Xie, Hui Hu, Fang Yu, Hui-lin Liu, Xing-yan Jiang, Han-dong Fan",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Molecular signal networks and regulating mechanisms of the unfolded protein response
%A Jing Gong
%A Xing-zhi Wang
%A Tao Wang
%A Jiao-jiao Chen
%A Xiao-yuan Xie
%A Hui Hu
%A Fang Yu
%A Hui-lin Liu
%A Xing-yan Jiang
%A Han-dong Fan
%J Journal of Zhejiang University SCIENCE B
%V 18
%N 1
%P 1-14
%@ 1673-1581
%D 2017
%I Zhejiang University Press & Springer

T1 - Molecular signal networks and regulating mechanisms of the unfolded protein response
A1 - Jing Gong
A1 - Xing-zhi Wang
A1 - Tao Wang
A1 - Jiao-jiao Chen
A1 - Xiao-yuan Xie
A1 - Hui Hu
A1 - Fang Yu
A1 - Hui-lin Liu
A1 - Xing-yan Jiang
A1 - Han-dong Fan
J0 - Journal of Zhejiang University Science B
VL - 18
IS - 1
SP - 1
EP - 14
%@ 1673-1581
Y1 - 2017
PB - Zhejiang University Press & Springer
ER -

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.



Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Awad, W., Estrada, I., Shen, Y., et al., 2008. BiP mutants that are unable to interact with endoplasmic reticulum Dnaj proteins provide insights into interdomain interactions in BiP. PNAS, 105(4):1164-1169.

[2]Bevilacqua, E., Wang, X., Majumder, M., et al., 2010. eIF2α phosphorylation tips the balance to apoptosis during osmotic stress. J. Biol. Chem., 285(22):17098-17111.

[3]Binet, F., Mawambo, G., Sitaras, N., et al., 2013. Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of netrin-1. Cell Metab., 17(3):353-371.

[4]Bommiasamy, H., Back, S.H., Fagone, P., et al., 2009. ATF6α induces XBP1-independent expansion of the endoplasmic reticulum. J. Cell Sci., 122(10):1626-1636.

[5]Braakman, I., Bulleid, N.J., 2011. Protein folding and modification in the mammalian endoplasmic reticulum. Annu. Rev. Biochem., 80(1):71-99.

[6]Cao, S.S., Zimmermann, E.M., Chuang, B.M., et al., 2013. The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. Gastroenterology, 144(5):S-989.

[7]Chaudhari, N., Talwar, P., Parimisetty, A., et al., 2014. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front. Cell. Neurosci., 8:213.

[8]Chen, L., Xu, S., Liu, L., et al., 2014a. Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell Death Dis., 5(5):e1219.

[9]Chen, X., Iliopoulos, D., Zhang, Q., et al., 2014b. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, 508(7494):103-107.

[10]Chung, K.T., Shen, Y., Hendershot, L.M., 2002. Bap, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J. Biol. Chem., 277(49):47557-47563.

[11]Cullinan, S.B., Zhang, D., Hannink, M., et al., 2003. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol., 23(20):7198-7209.

[12]Deng, J., Lu, P.D., Zhang, Y., et al., 2004. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol. Cell. Biol., 24(23):10161-10168.

[13]Drogat, B., Auguste, P., Nguyen, D.T., et al., 2007. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res., 67(14):6700-6707.

[14]Du, K., Takahashi, T., Kuge, S., et al., 2014. FBXO6 attenuates cadmium toxicity in HEK293 cells by inhibiting ER stress and JNK activation. J. Toxicol. Sci., 39(6):861-866.

[15]DuRose, J.B., Scheuner, D., Kaufman, R.J., et al., 2009. Phosphorylation of eukaryotic translation initiation factor 2α coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. Mol. Cell. Biol., 29(15):4295-4307.

[16]Eberle, A.B., Lykke-Andersen, S., Mühlemann, O., et al., 2009. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nat. Struct. Mol. Biol., 16(1):49-55.

[17]Eletto, D., Eletto, D., Dersh, D., et al., 2014. Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Mol. Cell, 53(4):562-576.

[18]Fabrizio, G., Di Paola, S., Stilla, A., et al., 2014. ARTC1-mediated ADP-ribosylation of GRP78/BiP: a new player in endoplasmic-reticulum stress responses. Cell. Mol. Life Sci., 72(6):1209-1225.

[19]Farhan, H., Weiss, M., Tani, K., et al., 2008. Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load. EMBO J., 27(15):2043-2054.

[20]Guo, F.J., Jiang, R., Li, X., et al., 2014a. Regulation of chondrocyte differentiation by IRE1α depends on its enzymatic activity. Cell. Signal., 26(9):1998-2007.

[21]Guo, F.J., Xiong, Z., Lu, X., et al., 2014b. ATF6 upregulates XBP1s and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage. Cell. Signal., 26(2):332-342.

[22]Häcker, G., 2014. ER-stress and apoptosis: molecular mechanisms and potential relevance in infection. Microbes Infect., 16(10):805-810.

[23]Harding, H.P., Zhang, Y., Scheuner, D., et al., 2009. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development. PNAS, 106(6):1832-1837.

[24]Hassler, J., Cao, S.S., Kaufman, R.J., 2012. IRE1, a double-edged sword in pre-miRNA slicing and cell death. Dev. Cell, 23(5):921-923.

[25]Hiramatsu, N., Messah, C., Han, J., et al., 2014. Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol. Biol. Cell, 25(9):1411-1420.

[26]Hirsch, I., Weiwad, M., Prell, E., et al., 2014. ERp29 deficiency affects sensitivity to apoptosis via impairment of the ATF6-CHOP pathway of stress response. Apoptosis, 19(5):801-815.

[27]Hu, P., Han, Z., Couvillon, A.D., et al., 2006. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression. Mol. Cell. Biol., 26(8):3071-3084.

[28]Huang, C.C., Li, Y., Lopez, A.B., et al., 2010. Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress. Biochem. J., 429(1):215-224.

[29]Hwang, J., Sato, H., Tang, Y., et al., 2010. UPF1 association with the CAP-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps. Mol. Cell, 39(3):396-409.

[30]Karali, E., Bellou, S., Stellas, D., et al., 2014. VEGF signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress. Mol. Cell, 54(4):559-572.

[31]Kaufman, R.J., 2004. Regulation of mRNA translation by protein folding in the endoplasmic reticulum. Trends Biochem. Sci., 29(3):152-158.

[32]Kaufman, R.J., Cao, S., 2010. Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism. EMBO Mol. Med., 2(6):189-192.

[33]Kim, J., Choi, T.G., Ding, Y., et al., 2008. Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca2+ homeostasis after ER stress. J. Cell Sci., 121(21):3636-3648.

[34]Kouroku, Y., Fujita, E., Tanida, I., et al., 2007. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ., 14(2):230-239.

[35]Li, M., Liu, Y., Xia, F., et al., 2014a. Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2. Cell. Signal., 26(7):1539-1548.

[36]Li, Y., Guo, Y., Tang, J., et al., 2014b. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim. Biophys. Sin. (Shanghai), 46(8):629-640.

[37]Lu, M., Lawrence, D.A., Marsters, S., et al., 2014. Cell death. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science, 345(6192):98-101.

[38]Majumder, M., Huang, C., Snider, M.D., et al., 2012. A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. Mol. Cell. Biol., 32(5):992-1003.

[39]Mak, B.C., Wang, Q., Laschinger, C., et al., 2008. Novel function of PERK as a mediator of force-induced apoptosis. J. Biol. Chem., 283(34):23462-23472.

[40]Malhotra, J.D., Kaufman, R.J., 2007. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal., 9(12):2277-2293.

[41]Malhotra, J.D., Kaufman, R.J., 2011. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb. Perspect. Biol., 3(9):a004424.

[42]Mao, T., Shao, M., Qiu, Y., et al., 2011. PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism. PNAS, 108(38):15852-15857.

[43]Maurel, M., Chevet, E., Tavernier, J., et al., 2014. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem. Sci., 39(5):245-254.

[44]Meares, G.P., Liu, Y., Rajbhandari, R., et al., 2014. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Mol. Cell. Biol., 34(20):3911-3925.

[45]Muaddi, H., Majumder, M., Peidis, P., et al., 2010. Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol. Biol. Cell, 21(18):3220-3231.

[46]Mühlemann, O., Lykke-Andersen, J., 2010. How and where are nonsense mRNAs degraded in mammalian cells? RNA Biol., 7(1):28-32.

[47]Nagasawa, K., Higashi, T., Hosokawa, N., et al., 2007. Simultaneous induction of the four subunits of the TRAP complex by ER stress accelerates ER degradation. EMBO Rep., 8(5):483-489.

[48]Nagelkerke, A., Bussink, J., Sweep, F.C., et al., 2014. The unfolded protein response as a target for cancer therapy. Biochim. Biophys. Acta, 1846(2):277-284.

[49]Niwa, M., Sidrauski, C., Kaufman, R.J., et al., 1999. A role for presenilin-1 in nuclear accumulation of IRE1 fragments and induction of the mammalian unfolded protein response. Cell, 99(7):691-702.

[50]Oslowski, C.M., Hara, T., O'sullivan-Murphy, B., et al., 2012. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab., 16(2):265-273.

[51]Poothong, J., Sopha, P., Kaufman, R.J., et al., 2010. Domain compatibility in IRE1 kinase is critical for the unfolded protein response. FEBS Lett., 584(14):3203-3208.

[52]Qiu, Y., Mao, T., Zhang, Y., et al., 2010. A crucial role for RACK1 in the regulation of glucose-stimulated IRE1α activation in pancreatic β cells. Sci. Signal., 3(106):ra7.

[53]Renna, M., Caporaso, M.G., Bonatti, S., et al., 2007. Regulation of ERGIC-53 gene transcription in response to endoplasmic reticulum stress. J. Biol. Chem., 282(31):22499-22512.

[54]Rutkowski, D.T., Kaufman, R.J., 2007. That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem. Sci., 32(10):469-476.

[55]Rutkowski, D.T., Arnold, S.M., Miller, C.N., et al., 2006. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol., 4(11):e374.

[56]Sakaki, K., Yoshina, S., Shen, X., et al., 2012. RNA surveillance is required for endoplasmic reticulum homeostasis. PNAS, 109(21):8079-8084.

[57]Shen, X., Zhang, K., Kaufman, R.J., 2004. The unfolded protein response—a stress signaling pathway of the endoplasmic reticulum. J. Chem. Neuroanat., 28(1-2):79-92.

[58]Shen, Y., Meunier, L., Hendershot, L.M., 2002. Identification and characterization of a novel endoplasmic reticulum (ER) Dnaj homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress. J. Biol. Chem., 277(18):15947-15956.

[59]Son, S.M., Byun, J., Roh, S.E., et al., 2014. Reduced IRE1α mediates apoptotic cell death by disrupting calcium homeostasis via the INSP3 receptor. Cell. Death Dis., 5(4):e1188.

[60]Sonenberg, N., Hinnebusch, A.G., 2009. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell, 136(4):731-745.

[61]Tsukumo, Y., Tsukahara, S., Furuno, A., et al., 2014. TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress. PLoS ONE, 9(11):e112761.

[62]Urra, H., Hetz, C., 2014. A novel ER stress-independent function of the UPR in angiogenesis. Mol. Cell, 54(4):542-544.

[63]Wang, M., Kaufman, R.J., 2014. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer, 14(9):581-597.

[64]Wang, S., Kaufman, R.J., 2012. The impact of the unfolded protein response on human disease. J. Cell Biol., 197(7):857-867.

[65]Wang, S., Chen, Z., Lam, V., et al., 2012. IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab., 16(4):473-486.

[66]Wang, W.A., Groenendyk, J., Michalak, M., 2014. Endoplasmic reticulum stress associated responses in cancer. BBA-Mol. Cell Res., 1843(10):2143-2149.

[67]Welihinda, A.A., Tirasophon, W., Green, S.R., et al., 1997. Gene induction in response to unfolded protein in the endoplasmic reticulum is mediated through Ire1p kinase interaction with a transcriptional coactivator complex containing Ada5p. PNAS, 94(9):4289-4294.

[68]Win, S., Than, T.A., Fernandez-Checa, J.C., et al., 2014. JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis., 5(1):e989.

[69]Wu, J., Ruas, J.L., Estall, J.L., et al., 2011. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metab., 13(2):160-169.

[70]Yadav, R.K., Chae, S.W., Kim, H.R., et al., 2014. Endoplasmic reticulum stress and cancer. J. Cancer Prev., 19(2):75-88.

[71]Yamamoto, K., Yoshida, H., Kokame, K., et al., 2004. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J. Biochem., 136(3):343-350.

[72]Zhang, K., Shen, X., Wu, J., et al., 2006. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell, 124(3):587-599.

[73]Zhang, P., Sun, Q., Zhao, C., et al., 2014. HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cell. Signal., 26(3):556-563.

[74]Zhu, J.J., Chai, X.L., Zhang, Y.S., 2014. Endoplasmic reticulum stress and vascular endothelial injury in type 2 diabetes mellitus. Progress Physiol. Sci., 45(1):72-74 (in Chinese).

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952276; Fax: +86-571-87952331; E-mail: jzus@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE