Endoplasmic reticulum is responsible for protein and lipid synthesis, processing and maturation within the cell. When a virus infects a cell, it also uses the endoplasmic reticulum to complete the protein synthesis of the virus itself. At the same time, the accumulation of large amounts of viral proteins induces stress responses in the endoplasmic reticulum, which then regulates various signalling pathways to maintain cellular homeostasis, leading to autophagy, apoptosis and metabolic syndrome. Some viruses enhance their own replication by altering the expression of proteins in stress pathways that are detrimental to their replication, at the same time maintaining aspects that are beneficial to them. In this paper, we provide a brief review of endoplasmic reticulum stress and unfolded protein response signalling pathways and the interactions between some viral infections and endoplasmic reticulum stress and some metabolic syndromes caused by viral infections and summarize the latest findings on endoplasmic reticulum stress and viral infections with the aim of providing ideas for endoplasmic reticulum stress-related antiviral infections research.

Meiqi Kang, Qinglu Zhao, Hui Zhang, Shuzhen Liu, Zhiru Gao, Zhihui Hu, Rui Zhang. Endoplasmic Reticulum Stress and Viral Infections. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 12: 14-21. https://doi.org/10.25236/IJFM.2024.061203.

[1] Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation [J]. Science, 2011, 334 (6059): 1081-1086.

[2] Travers K J, Patil C K, Wodicka L, et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation [J]. Cell, 2000, 101(3):249 - 258.

[3] Shen J S, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals [J]. Developmental Cell, 2002, 3(1): 99-111.

[4] Bertolotti A, Zhang Y, Hendershot L M, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response [J]. Nature Cell Biology, 2000, 2(6): 326 - 332.

[5] He B. Viruses, endoplasmic Reticulum stress, and interferon responses [J]. Cell Death & Differentiation, 2006, 13 (3): 393 -403.

[6] van Huizen R, Martindale J L, Gorospe M, et al. P58IPK, a novel endoplasmic Reticulum stress-inducible protein and potential negative regulator of eIF2α signaling [J]. Journal of Biological Chemistry, 2003, 278(18): 15558 - 15564. 

[7] Novoa I, Zhang Y H, Zeng H Q, et al. Stress-induced gene expression requires programmed recovery from translational repression [J]. The EMBO Journal, 2003, 22(5): 1180 - 1187.

[8] Harding H P, Novoa I, Zhang Y H, et al. Regulated translation initiation controls stress-induced   gene expression in mammalian cells [J]. Molecular Cell, 2000, 6(5): 1099 - 1108.

[9] Ma Y J, Hendershot L M. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic Reticulum stress [J]. Journal of Biological Chemistry, 2003, 278 (37): 34864 - 34873.

[10] McCullough K D, Martindale J L, Klotz L O, et al. Gadd153 sensitizes cells to endoplasmic Reticulum stress by down - regulating Bcl2 and perturbing the cellular redox state [J]. Molecular and Cellular Biology, 2001, 21(4): 1249 - 1259.

[11] Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic Reticulum stress [J]. Nature Cell Biology, 2011, 13 (3): 184 - 190.

[12] Brush M H, Weiser D C, Shenolikar S. Growth arrest and DNA damage- inducible protein GADD34  targets protein phosphatase 1alpha to the endoplasmic Reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 [J]. Molecular and Cellular Biology, 2003, 23(4): 1292 - 1303. 

[13] Lee K, Tirasophon W, Shen X H, et al. IRE1-mediated unconventional mRNA splicing and S2P - mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response [J]. Genes & Development, 2002, 16(4): 452 - 466.

[14] Lee A H, Iwakoshi N N, Glimcher L H. XBP - 1 regulates a subset of endoplasmic Reticulum resident chaperone genes in the unfolded protein response [J]. Molecular and Cellular Biology, 2003, 23 (21): 7448 - 7459.

[15] Deegan S, Saveljeva S, Gorman A M, et al. Stress-induced self-cannibalism: on the regulation of   autophagy by endoplasmic Reticulum stress [J]. Cellular and Molecular Life Sciences: CMLS, 2013, 70(14): 2425 - 2441.

[16] Senft D, Ronai Z A. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response [J]. Trends in Biochemical Sciences, 2015, 40(3): 141 - 148.

[17] B'chir W, Maurin A C, Carraro V, et al. The eIF2α/ATF4 pathway is essential for stress-induced   autophagy gene expression [J]. Nucleic Acids Research, 2013, 41(16): 7683 - 7699.

[18] Christianson J C, Ye Y. Cleaning up in the endoplasmic Reticulum: ubiquitin in charge [J]. Nature Structural & Molecular Biology, 2014, 21(4): 325 - 335.

[19] Ruggiano A, Foresti O, Carvalho P. Quality control: ER - associated degradation: protein quality control and beyond [J]. The Journal of Cell Biology, 2014, 204(6): 869 - 879.

[20] Teckman J H, Perlmutter D H. Retention of mutant alpha(1) - antitrypsin Z in endoplasmic Reticulum is associated with an autophagic response [J]. American Journal of Physiology. Gastrointestinal and Liver Physiology, 2000, 279(5): G961 - G974.  

[21] Houck S A, Ren H Y, Madden V J, et al. Quality control autophagy degrades soluble ERAD-resistant   conformers of the misfolded membrane protein GnRHR [J]. Molecular Cell, 2014, 54 (1):166 - 179.

[22] Muzio M, Chinnaiyan A M, Kischkel F C, et al.  FLICE, A novel FADD-homologous ICE/CED-3-like protease is recruited to the CD95 (fas/APO - 1) death-inducing signaling complex [J].Cell, 1996, 85(6): 817 - 82.

[23] Kischkel F C, Hellbardt S, Behrmann I, et al. Cytotoxicity-dependent APO-1 ( Fas/CD95 ) -  associated proteins form a death - inducing signaling complex ( DISC) with the receptor[J]. The EMBO Journal, 1995, 14(22): 5579 - 5588.

[24] Zou H, Li Y, Liu X, et al. An APAF-1. Cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9 [J]. The Journal of Biological Chemistry, 1999, 274(17): 11549 -11556.

[25] Ferri K F, Kroemer G. Organelle-specific initiation of cell death pathway [J]. Nature Cell Biology, 2001, 3(11): E255 - E263.

[26] Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1[J]. Science, 2000, 287(5453): 664 - 666.

[27] Tournier C, Hess P, Yang D D, et al. Requirement of JNK for stress-induced activation of the cytochrome c -mediated death pathway [J]. Science, 2000, 288(5467): 870 - 874.

[28] Häcki J, Egger L, Monney L, et al. Apoptotic crosstalk between the endoplasmic Reticulum and mitochondria controlled by bcl-2[J].Oncogene, 2000, 19(19): 2286 - 2295.

[29] Tagami S, Eguchi Y, Kinoshita M, et al. A novel protein, RT-xS, interacts with both Bcl-xL and Bcl-2 on endoplasmic Reticulum and reduces their anti-apoptotic activity [J]. Oncogene, 2000, 19 (50): 5736 - 5746.

[30] Peña J, Harris E. Dengue virus modulates the unfolded protein response in a time-dependent manner [J]. Journal of Biological Chemistry, 2011, 286(16): 14226 - 14236.

[31] Umareddy I, Pluquet O, Wang Q Y, et al. Dengue virus serotype infection specifies the activation of the unfolded protein response [J]. Virology Journal, 2007, 4: 91. 

[32] Yu C Y, Hsu Y W, Liao C L, et al. Flavivirus infection activates the XBP1 pathway of the unfolded   protein response to cope with endoplasmic Reticulum stress [J]. Journal of Virology, 2006, 80 (23): 11868 - 11880.

[33] Datan E, Roy S G, Germain G, et al. Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation [J]. Cell Death & Disease, 2016, 7 (3):e2127.

[34] Jain B, Chaturvedi U C, Jain A. Role of intracellular events in the pathogenesis of dengue: an overview [J]. Microbial Pathogenesis, 2014, 69/70: 45 - 52. 

[35] Perera N, Miller J L, Zitzmann N. The role of the unfolded protein response in dengue virus pathogenesis [J]. Cellular Microbiology, 2017, 19(5):e12734.

[36] Liberman E, Fong Y L, Selby M J, et al. Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein [J]. Journal of Virology, 1999, 73(5): 3718 - 3722.

[37] Tardif K D, Mori K, Siddiqui A. Hepatitis C virus subgenomic replicons induce endoplasmic    Reticulum stress activating an intracellular signaling pathway [J]. Journal of Virology, 2002, 76 (15): 7453 - 7459.

[38] Ke P Y, Chen S S L. Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro [J]. The Journal of Clinical Investigation, 2011, 121(1): 37 - 56.

[39] Ye S Y, Li Z H, Chen F Z, et al. Porcine epidemic diarrhea virus ORF3 gene prolongs S - phase , facilitates formation of vesicles and promotes the proliferation of attenuated PEDV [ J]. Virus Genes, 2015, 51(3): 385 - 392.

[40] Liao Y, Fung T S, Huang M, et al. Upregulation of CHOP/GADD153 during coronavirus infectious  bronchitis virus infection modulates apoptosis by restricting activation of the extracellular signal-regulated kinase pathway[J]. Journal of Virology, 2013, 87(14): 8124 - 8134. 

[41] Xu Z, Jensen G, Yen T S. Activation of hepatitis B virus S promoter by the viral large surface protein  via induction of stress in the endoplasmic Reticulum [J]. Journal of Virology, 1997, 71 (10): 7387 - 7392.

[42] Li Y, Xia Y C, Cheng X M, et al. Hepatitis B surface antigen activates unfolded protein response in forming ground glass hepatocytes of chronic hepatitis B [J]. Viruses, 2019, 11(4): 386.

[43] Gerber M A, Hadziyannis S, Vissoulis C, et al. Electron microscopy and immunoelectron microscopy of cytoplasmic hepatitis B antigen in hepatocytes[J]. The American Journal of Pathology, 1974, 75(3): 489 - 502.

[44] Isler J A, Skalet A H, Alwine J C. Human Cytomegalovirus infection activates and regulates the unfolded protein response [J]. Journal of Virology, 2005, 79(11): 6890 - 6899.

[45] Luganini A, di Nardo G, Munaron L, et al. Human Cytomegalovirus US21 protein is a viroporin that modulates calcium homeostasis and protects cells against apoptosis [J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (52): E12370 - E12377.

[46] Yang S B, Zhu J J, Zhou X L, et al. Induction of the unfolded protein response ( UPR) during  pseudorabies virus infection [J]. Veterinary Microbiology, 2019, 239: 108485.

[47] Ouyang Y L, Xu L, Lü J M, et al. Porcine Circovirus type 2 ORF5 protein induces endoplasmic Reticulum stress and unfolded protein response in porcine alveolar macrophages [J]. Archives of Virology, 2019, 164(5): 1323 - 1334.

[48] Zhou Y S, Qi B Z, Gu Y X, et al. Porcine Circovirus 2 deploys PERK pathway and GRP78 for its enhanced replication in PK - 15 cells [J]. Viruses, 2016, 8(2): 56.

[49] Berger E, Haller D. Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic Reticulum stress in intestinal epithelial cells [J]. Biochemical and Biophysical Research Communications, 2011, 409(4): 610 - 615.

[50] Fu S N, Watkins S M, Hotamisligil G S. The role of endoplasmic Reticulum in hepatic lipid homeostasis and stress signaling [J]. Cell Metabolism, 2012, 15(5): 623 - 634.

[51] Brown M S, Goldstein J L. Cholesterol feedback: from schoenheimer's bottle to scap's MELADL [J]. Journal of Lipid Research, 2009, 50: S15 - S27.

[52] Sun X J, Rothenberg P, Kahn C R, et al. Structure of the insulin receptor substrate IRS -1 defines a unique signal transduction protein [J]. Nature, 1991, 352(6330): 73 - 77.

[53] Mota M, Banini B A, Cazanave S C, et al. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease[ J]. Metabolism, 2016, 65(8): 1049 - 1061.

[54] Cai Y, Arikkath J, Yang L, et al. Interplay of endoplasmic Reticulum stress and autophagy in neurodegenerative disorders [J]. Autophagy, 2016, 12(2): 225 - 244.

[55] Cheng G F, Feng Z D, He B. Herpes simplex virus 1 infection activates the endoplasmic Reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma (1)34.5 Protein [J]. Journal of Virology, 2005, 79(3): 1379 - 1388.