新型冠狀病毒是一種新型傳染性病原體，自 2019 年以來一直是重大突發公共衛生事件和全球大流行的原因。在嚴重的 COVID-19 患者中可以觀察到過度炎症，隨著時間的推移導致急性呼吸窘迫綜合徵 (ARDS) 和肺纖維化 . 被感染時，病毒蛋白是通過宿主的細胞機制產生的，包括刺突蛋白 (S)，它嚴重依賴內質網 (ER) 伴護蛋白，並已被證明會在 SARS-CoV-1 中誘導 ER 壓力。 此外，該病毒可通過其 S 直接觸發肺部浸潤性中性粒細胞的 NETosis。據報導，在受感染細胞表面表達的 S 有助於合胞體形成。 然而，關於膜 S 在 NETosis 進展中的作用知之甚少。 在我們的研究中，我們發現 S 定位於 ER 並且 S 的過表達選擇性地激活了未折疊蛋白反應（UPR）的 PERK 和 IRE1α 分支，導致 C/EBP 同源蛋白（CHOP）表現上升和 X-box 結合蛋白 1 (XBP1) 的可變剪接。 在 S 過表達細胞中也檢測到活性氧 (ROS) 水平升高。 此外，已經證明CHOP在調節內質網壓力誘導的細胞凋亡中起著至關重要的作用，然而我們發現，在S過度表達時，B細胞淋巴瘤-2（BCL-2）基因在RNA水平上調。這表明，S誘導的內質網壓力不足以觸發細胞凋亡。接下來，為了驗證膜S對NETosis誘導的影響，我們發現S表達在轉染的293T和A549細胞的表面。有趣的是，在加入內質網壓力抑制劑後，表面S的表現量有所下降。在我們的共培養模型中，我們觀察到NETosis標記物CD66b的增加，以及髓過氧化物酶（MPO）和白細胞介素8（IL-8）的釋放，這表明膜S能夠誘導NETosis和中性粒細胞脫顆粒。此外，重組血管緊張素轉化酶2（ACE2）的添加顯著減少了S誘導的共培養中的NETosis，這表明ACE2可能作為受體與S相互作用，負責中性粒細胞的活化。有趣的是，隨著時間的推移，S的表達減少，證明NETosis可能在調節S的清除中發揮作用。總而言之，內源性S的表達激活了細胞內的內質網壓力和增加了活性氧，而通過內質網壓力將S表現在細胞膜上，進而刺激中性粒細胞的活化和NETosis。

SARS-CoV-2 is a novel infectious agent that has been the cause of major public health emergencies and global pandemics since 2019. Hyperinflammation is observed in severe COVID-19 patients, leading to acute respiratory distress syndrome (ARDS) and pulmonary fibrosis over time. While infected, viral proteins are produced via the hosts’ cellular machinery, including the spike protein (S), which heavily relies on endoplasmic reticulum (ER) protein chaperones and has been shown to induce ER stress in SARS-CoV-1. In addition, the virus can directly trigger NETosis in lung infiltrating neutrophils via its S. It has been reported that S expressed on the surface of infected cells contributes to syncytia formation. However, little is known about the role of membrane S in the progression of NETosis. In our study, we revealed that S localized in the ER and overexpression of S selectively activated the PERK and IRE1α branch of the unfolded protein response (UPR), leading to an upregulation of the expression of C/EBP homologous protein (CHOP) and the alternative splicing of X-box binding protein 1 (XBP1), respectively. Increased reactive oxygen species (ROS) levels were also detected in S-overexpressed cells. Furthermore, it has been shown that CHOP plays a vital role in regulating ER stress-induced apoptosis. However, we found that the B-cell lymphoma-2 (BCL-2) gene upregulated at RNA level when S was overexpressed, indicating that S-induced ER stress is insufficient to trigger cellular apoptosis. Next, to verify the effect of membrane S on NETosis induction, we revealed that S expressed on the surface of transfected 293T and A549 cells. Interestingly, the surface S level decreased upon treatment with an ER stress inhibitor. In our coculture model, we observed an increase in the NETosis marker CD66b, as well as the release of myeloperoxidase (MPO) and interleukin 8 (IL-8) at 1hr, suggesting that the membrane S was capable of inducing NETosis and neutrophil degranulation. Moreover, the addition of recombinant angiotensin-converting enzyme 2 (ACE2) significantly reduced S-induced NETosis in co-culture, indicating that ACE2 may serve as the receptor responsible for neutrophil activation through interaction with S. Interestingly, a decrease of S expression was observed over time, demonstrating that NETosis may play a role in regulating S clearance. In summary, intracellular S expression activates ER stress and elevated ROS within cells, while S is displayed on the cell membrane through ER stress, stimulating neutrophil activation and NETosis.

Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D., & Zychlinsky, A. (2012). Neutrophil function: From mechanisms to disease. Annual Review of Immunology (Vol. 30, pp. 459–489). https://doi.org/10.1146/annurev-immunol-020711-074942
Avolio, E., Carrabba, M., Milligan, R., Williamson, M. K., Beltrami, A. P., Gupta, K., Elvers, K. T., Gamez, M., Foster, R. R., Gillespie, K., Hamilton, F., Arnold, D., Berger, I., Davidson, A. D., Hill, D., Caputo, M., & Madeddu, P. (2021). The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: A potential non-infective mechanism of COVID-19 microvascular disease. Clinical Science, 135(24), 2667–2689. https://doi.org/10.1042/CS20210735
Barnes, B. J., Adrover, J. M., Baxter-Stoltzfus, A., Borczuk, A., Cools-Lartigue, J., Crawford, J. M., Daßler-Plenker, J., Guerci, P., Huynh, C., Knight, J. S., Loda, M., Looney, M. R., McAllister, F., Rayes, R., Renaud, S., Rousseau, S., Salvatore, S., Schwartz, R. E., Spicer, J. D., … Egeblad, M. (2020). Targeting potential drivers of COVID-19: Neutrophil extracellular traps. Journal of Experimental Medicine (Vol. 217, Issue 6). Rockefeller University Press. https://doi.org/10.1084/jem.20200652
Bayati, A., Kumar, R., Francis, V., & McPherson, P. S. (2021). SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. Journal of Biological Chemistry (Vol. 296). American Society for Biochemistry and Molecular Biology Inc. https://doi.org/10.1016/j.jbc.2021.100306
Belouzard, S., Millet, J. K., Licitra, B. N., & Whittaker, G. R. (2012). Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses (Vol. 4, Issue 6, pp. 1011–1033). https://doi.org/10.3390/v4061011
Biwer, L. A., & Isakson, B. E. (2017). Endoplasmic reticulum-mediated signalling in cellular microdomains. Acta Physiologica (Vol. 219, Issue 1, pp. 162–175). Blackwell Publishing Ltd. https://doi.org/10.1111/apha.12675
Bommiasamy, H., Back, S. H., Fagone, P., Lee, K., Meshinchi, S., Vink, E., Sriburi, R., Frank, M., Jackowski, S., Kaufman, R. J., & Brewer, J. W. (2009). ATF6α induces XBP1-independent expansion of the endoplasmic reticulum. Journal of Cell Science, 122(10), 1626–1636. https://doi.org/10.1242/jcs.045625
Bonaventura, A., Vecchié, A., Dagna, L., Martinod, K., Dixon, D. L., Van Tassell, B. W., Dentali, F., Montecucco, F., Massberg, S., Levi, M., & Abbate, A. (2021). Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nature Reviews Immunology. https://doi.org/10.1038/s41577-021-00536-9
Borregaard, N. (2010). Neutrophils, from Marrow to Microbes. In Immunity (Vol. 33, Issue 5, pp. 657–670). https://doi.org/10.1016/j.immuni.2010.11.011
Braakman, I., & Hebert, D. N. (2013). Protein folding in the endoplasmic reticulum. Cold Spring Harbor Perspectives in Biology, 5(5). https://doi.org/10.1101/cshperspect.a013201
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., Weinrauch, Y., & Zychlinsky, A. (2004). Neutrophil extracellular traps kill bacteria. Science (New York, N.Y.), 303(5663), 1532–1535. https://doi.org/10.1126/science.1092385
Buchrieser, J., Dufloo, J., Hubert, M., Monel, B., Planas, D., Rajah, M. M., Planchais, C., Porrot, F., Guivel‐Benhassine, F., Van der Werf, S., Casartelli, N., Mouquet, H., Bruel, T., & Schwartz, O. (2020). Syncytia formation by SARS‐CoV‐2‐infected cells. The EMBO Journal, 39(23). https://doi.org/10.15252/embj.2020106267
Cesta, M. C., Zippoli, M., Marsiglia, C., Gavioli, E. M., Cremonesi, G., Khan, A., Mantelli, F., Allegretti, M., & Balk, R. (2023). Neutrophil activation and neutrophil extracellular traps (NETs) in COVID-19 ARDS and immunothrombosis. European Journal of Immunology (Vol. 53, Issue 1). John Wiley and Sons Inc. https://doi.org/10.1002/eji.202250010
Chan, C.-P., Siu, K.-L., Chin, K.-T., Yuen, K.-Y., Zheng, B., & Jin, D.-Y. (2006). Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. Journal of Virology, 80(18), 9279–9287. https://doi.org/10.1128/jvi.00659-06
Chen, K., Nishi, H., Travers, R., Tsuboi, N., Martinod, K., Wagner, D. D., Stan, R., Croce, K., & Mayadas, T. N. (2012). Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo. Blood, 120(22), 4421–4431. https://doi.org/10.1182/blood-2011-12-401133
Ching, K. L., de Vries, M., Gago, J., Dancel-Manning, K., Sall, J., Rice, W. J., Barnett, C., Khodadadi-Jamayran, A., Tsirigos, A., Liang, F. X., Thorpe, L. E., Shopsin, B., Segal, L. N., Dittmann, M., Torres, V. J., & Cadwell, K. (2022). ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection. PLoS Biology, 20(9). https://doi.org/10.1371/journal.pbio.3001754
El-Shennawy, L., Hoffmann, A. D., Dashzeveg, N. K., McAndrews, K. M., Mehl, P. J., Cornish, D., Yu, Z., Tokars, V. L., Nicolaescu, V., Tomatsidou, A., Mao, C., Felicelli, C. J., Tsai, C. F., Ostiguin, C., Jia, Y., Li, L., Furlong, K., Wysocki, J., Luo, X., … Liu, H. (2022). Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nature Communications, 13(1). https://doi.org/10.1038/s41467-021-27893-2
Fagone, P., & Jackowski, S. (2009). Membrane phospholipid synthesis and endoplasmic reticulum function. Journal of Lipid Research, 50 Suppl(Suppl), S311-6. https://doi.org/10.1194/jlr.R800049-JLR200
Fukushi, M., Yoshinaka, Y., Matsuoka, Y., Hatakeyama, S., Ishizaka, Y., Kirikae, T., Sasazuki, T., & Miyoshi-Akiyama, T. (2012). Monitoring of S Protein Maturation in the Endoplasmic Reticulum by Calnexin Is Important for the Infectivity of Severe Acute Respiratory Syndrome Coronavirus. Journal of Virology, 86(21), 11745–11753. https://doi.org/10.1128/jvi.01250-12
Gadanec, L. K., McSweeney, K. R., Qaradakhi, T., Ali, B., Zulli, A., & Apostolopoulos, V. (2021). Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells? International Journal of Molecular Sciences, 22(3). https://doi.org/10.3390/ijms22030992
George, S., Pal, A. C., Gagnon, J., Timalsina, S., Singh, P., Vydyam, P., Munshi, M., Chiu, J. E., Renard, I., Harden, C. A., Ott, I. M., Watkins, A. E., Vogels, C. B. F., Lu, P., Tokuyama, M., Venkataraman, A., Casanovas-Massana, A., Wyllie, A. L., Rao, V., … and the Yale IMPACT Team. (2021). Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 Patients. Kidney360, 2(6), 924–936. https://doi.org/10.34067/KID.0002172021
Glowacka, I., Bertram, S., Müller, M. A., Allen, P., Soilleux, E., Pfefferle, S., Steffen, I., Tsegaye, T. S., He, Y., Gnirss, K., Niemeyer, D., Schneider, H., Drosten, C., & Pöhlmann, S. (2011). Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response. Journal of Virology, 85(9), 4122–4134. https://doi.org/10.1128/jvi.02232-10
Görlach, A., Klappa, P., & Kietzmann, T. (2006). The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxidants & Redox Signaling, 8(9–10), 1391–1418. https://doi.org/10.1089/ars.2006.8.1391
Harding, H. P., Zhang, Y., & Ron, D. (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397(6716), 271–274. https://doi.org/10.1038/16729
Harrison, A. G., Lin, T., & Wang, P. (2020). Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends in Immunology (Vol. 41, Issue 12, pp. 1100–1115). Elsevier Ltd. https://doi.org/10.1016/j.it.2020.10.004
Hartenian, E., Nandakumar, D., Lari, A., Ly, M., Tucker, J. M., & Glaunsinger, B. A. (2020). The molecular virology of coronaviruses. Journal of Biological Chemistry (Vol. 295, Issue 37, pp. 12910–12934). American Society for Biochemistry and Molecular Biology Inc. https://doi.org/10.1074/jbc.REV120.013930
Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature (Vol. 475, Issue 7356, pp. 324–332). https://doi.org/10.1038/nature10317
Haze, K., Yoshida, H., Yanagi, H., Yura, T., & Mori, K. (1999). Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Molecular Biology of the Cell, 10(11), 3787–3799. https://doi.org/10.1091/mbc.10.11.3787
Hetz, C., Zhang, K., & Kaufman, R. J. (2020). Mechanisms, regulation and functions of the unfolded protein response. Nature Reviews Molecular Cell Biology (Vol. 21, Issue 8, pp. 421–438). Nature Research. https://doi.org/10.1038/s41580-020-0250-z
Hollien, J., Lin, J. H., Li, H., Stevens, N., Walter, P., & Weissman, J. S. (2009). Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. Journal of Cell Biology, 186(3), 323–331. https://doi.org/10.1083/jcb.200903014
Horimoto, S., Ninagawa, S., Okada, T., Koba, H., Sugimoto, T., Kamiya, Y., Kato, K., Takeda, S., & Mori, K. (2013). The unfolded protein response transducer ATF6 represents a novel transmembrane-type endoplasmic reticulum-associated degradation substrate requiring both mannose trimming and SEL1L protein. Journal of Biological Chemistry, 288(44), 31517–31527. https://doi.org/10.1074/jbc.M113.476010
Hu, B., Guo, H., Zhou, P., & Shi, Z. L. (2021). Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology (Vol. 19, Issue 3, pp. 141–154). Nature Research. https://doi.org/10.1038/s41579-020-00459-7
Huang, I. C., Bosch, B. J., Li, F., Li, W., Kyoung, H. L., Ghiran, S., Vasilieva, N., Dermody, T. S., Harrison, S. C., Dormitzer, P. R., Farzan, M., Rottier, P. J. M., & Choe, H. (2006). SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. Journal of Biological Chemistry, 281(6), 3198–3203. https://doi.org/10.1074/jbc.M508381200
Huang, Z.-M., Tan, T., Yoshida, H., Mori, K., Ma, Y., & Yen, T. S. B. (2005). Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress. Molecular and Cellular Biology, 25(17), 7522–7533. https://doi.org/10.1128/mcb.25.17.7522-7533.2005
Irigoyen, N., Firth, A. E., Jones, J. D., Chung, B. Y. W., Siddell, S. G., & Brierley, I. (2016). High-Resolution Analysis of Coronavirus Gene Expression by RNA Sequencing and Ribosome Profiling. PLoS Pathogens, 12(2). https://doi.org/10.1371/journal.ppat.1005473
Jackson, C. B., Farzan, M., Chen, B., & Choe, H. (2022). Mechanisms of SARS-CoV-2 entry into cells. Nature Reviews Molecular Cell Biology (Vol. 23, Issue 1, pp. 3–20). Nature Research. https://doi.org/10.1038/s41580-021-00418-x
John-Paul Upton, Likun Wang, Dan Han, Eric S Wang, Noelle E Huskey, Lionel Lim, Morgan Truitt, Michael T McManus, Davide Ruggero, Andrei Goga, Feroz R Papa, & Scott A Oakes. (2012). IRE1a Cleaves Select microRNAsDuring ER Stress to DerepressTranslation of Proapoptotic Caspase-2. Science, 338(6108), 815–818. https://doi.org/10.1126/science.1225625
Julie Hollien, & Jonathan S. Weissman. (2006). Decay of EndoplasmicReticulum-Localized mRNAs Duringthe Unfolded Protein Response. Science, 313(5783), 101–104. https://doi.org/10.1126/science.1126121
Kaufman, R. J., Scheuner, D., Schröder, M., Shen, X., Lee, K., Liu, C. Y., & Arnold, S. M. (2002). The unfolded protein response in nutrient sensing and differentiation. Nature Reviews Molecular Cell Biology (Vol. 3, Issue 6, pp. 411–421). https://doi.org/10.1038/nrm829
Kedersha, N., Chen, S., Gilks, N., Li, W., Miller, I. J., Stahl, J., & Anderson, P. (2002). Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules. Molecular Biology of the Cell, 13(1), 195–210. https://doi.org/10.1091/mbc.01-05-0221
Knoops, K., Kikkert, M., Van Den Worm, S. H. E., Zevenhoven-Dobbe, J. C., Van Der Meer, Y., Koster, A. J., Mommaas, A. M., & Snijder, E. J. (2008). SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biology, 6(9), 1957–1974. https://doi.org/10.1371/journal.pbio.0060226
Kolaczkowska, E., & Kubes, P. (2013). Neutrophil recruitment and function in health and inflammation. Nature Reviews Immunology (Vol. 13, Issue 3, pp. 159–175). https://doi.org/10.1038/nri3399
Lacy, P. (2006). Mechanisms of degranulation in neutrophils. Allergy, Asthma and Clinical Immunology (Vol. 2, Issue 3, pp. 98–108). https://doi.org/10.2310/7480.2006.00012
Lamers, M. M., & Haagmans, B. L. (2022). SARS-CoV-2 pathogenesis. Nature Reviews Microbiology (Vol. 20, Issue 5, pp. 270–284). Nature Research. https://doi.org/10.1038/s41579-022-00713-0
Lauer, S. A., Grantz, K. H., Bi, Q., Jones, F. K., Zheng, Q., Meredith, H. R., Azman, A. S., Reich, N. G., & Lessler, J. (2020). The incubation period of coronavirus disease 2019 (CoVID-19) from publicly reported confirmed cases: Estimation and application. Annals of Internal Medicine, 172(9), 577–582. https://doi.org/10.7326/M20-0504
Lee, A.-H., Iwakoshi, N. N., & Glimcher, L. H. (2003). XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response. Molecular and Cellular Biology, 23(21), 7448–7459. https://doi.org/10.1128/mcb.23.21.7448-7459.2003
Lin, J. H., Walter, P., & Yen, T. S. B. (2008). Endoplasmic reticulum stress in disease pathogenesis. Annual Review of Pathology: Mechanisms of Disease (Vol. 3, pp. 399–425). https://doi.org/10.1146/annurev.pathmechdis.3.121806.151434
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., … Tan, W. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet, 395(10224), 565–574. https://doi.org/10.1016/S0140-6736(20)30251-8
Calfon, M., Zeng, H., Urano, F., Till, J. H., Hubbard, S. R., Harding, H. P., Clark, S. G., & Ron, D. (2002). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 415(6867), 92–96. https://doi.org/10.1038/415092a
Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P., & Ron, D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes and Development, 18(24), 3066–3077. https://doi.org/10.1101/gad.1250704
Martinod, K., & Wagner, D. D. (2014). Thrombosis: tangled up in NETs. Blood, 123(18), 2768–2776. https://doi.org/10.1182/blood-2013-10-463646
Masters, P. S. (2006). The Molecular Biology of Coronaviruses. Advances in Virus Research (Vol. 65, pp. 193–292). https://doi.org/10.1016/S0065-3527(06)66005-3
Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A., & Papayannopoulos, V. (2014). Myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Reports, 8(3), 883–896. https://doi.org/10.1016/j.celrep.2014.06.044
Mulay, A., Konda, B., Garcia, G., Yao, C., Beil, S., Villalba, J. M., Koziol, C., Sen, C., Purkayastha, A., Kolls, J. K., Pociask, D. A., Pessina, P., de Aja, J. S., Garcia-de-Alba, C., Kim, C. F., Gomperts, B., Arumugaswami, V., & Stripp, B. R. (2021). SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. Cell Reports, 35(5). https://doi.org/10.1016/j.celrep.2021.109055
Nair, K. S., & Zingde, S. M. (2001). Adhesion of neutrophils to fibronectin: Role of the CD66 antigens. Cellular Immunology, 208(2), 96–106. https://doi.org/10.1006/cimm.2001.1772
Nardacci, R., Perfettini, J. L., Grieco, L., Thieffry, D., Kroemer, G., & Piacentini, M. (2015). Syncytial apoptosis signaling network induced by the HIV-1 envelope glycoprotein complex: An overview. Cell Death and Disease (Vol. 6). Nature Publishing Group. https://doi.org/10.1038/cddis.2015.204
Ng, H., Havervall, S., Rosell, A., Aguilera, K., Parv, K., Von Meijenfeldt, F. A., Lisman, T., Mackman, N., Thålin, C., & Phillipson, M. (2021). Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients with COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology, 988–994. https://doi.org/10.1161/ATVBAHA.120.315267
Nikawa, J., & Yamashita, S. (1992). IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae. Molecular Microbiology, 6(11), 1441–1446. https://doi.org/10.1111/j.1365-2958.1992.tb00864.x
Ning, Q., Wu, D., Wang, X., Xi, D., Chen, T., Chen, G., Wang, H., Lu, H., Wang, M., Zhu, L., Hu, J., Liu, T., Ma, K., Han, M., & Luo, X. (2022). The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication. Signal Transduction and Targeted Therapy (Vol. 7, Issue 1). Springer Nature. https://doi.org/10.1038/s41392-022-00907-1
Oakes, S. A., & Papa, F. R. (2015). The role of endoplasmic reticulum stress in human pathology. Annual Review of Pathology: Mechanisms of Disease, 10, 173–194. https://doi.org/10.1146/annurev-pathol-012513-104649
Oyadomari, S., Yun, C., Fisher, E. A., Kreglinger, N., Kreibich, G., Oyadomari, M., Harding, H. P., Goodman, A. G., Harant, H., Garrison, J. L., Taunton, J., Katze, M. G., & Ron, D. (2006). Cotranslocational Degradation Protects the Stressed Endoplasmic Reticulum from Protein Overload. Cell, 126(4), 727–739. https://doi.org/10.1016/j.cell.2006.06.051
Peña, J., & Harris, E. (2011). Dengue virus modulates the unfolded protein response in a time-dependent manner. Journal of Biological Chemistry, 286(16), 14226–14236. https://doi.org/10.1074/jbc.M111.222703
Plant, E. P., Sims, A. C., Baric, R. S., Dinman, J. D., & Taylor, D. R. (2013). Altering SARS coronavirus frameshift efficiency affects genomic and subgenomic RNA production. Viruses, 5(1), 279–294. https://doi.org/10.3390/v5010279
Rajah, M. M., Bernier, A., Buchrieser, J., & Schwartz, O. (2022). The Mechanism and Consequences of SARS-CoV-2 Spike-Mediated Fusion and Syncytia Formation. Journal of Molecular Biology (Vol. 434, Issue 6). Academic Press. https://doi.org/10.1016/j.jmb.2021.167280
Ron, D., & Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews Molecular Cell Biology (Vol. 8, Issue 7, pp. 519–529). https://doi.org/10.1038/nrm2199
Sciarretta, S., Zhai, P., Shao, D., Zablocki, D., Nagarajan, N., Terada, L. S., Volpe, M., & Sadoshima, J. (2013). Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway. Circulation Research, 113(11), 1253–1264. https://doi.org/10.1161/CIRCRESAHA.113.301787
Shaffer, A. L., Shapiro-Shelef, M., Iwakoshi, N. N., Lee, A.-H., Qian, S.-B., Zhao, H., Yu, X., Yang, L., Tan, B. K., Rosenwald, A., Hurt, E. M., Petroulakis, E., Sonenberg, N., Yewdell, J. W., Calame, K., Glimcher, L. H., & Staudt, L. M. (2004). XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 21(1), 81–93. https://doi.org/10.1016/j.immuni.2004.06.010
Shamu, C. E., & Walter, P. (1996). Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. The EMBO Journal, 15(12), 3028–3039. http://www.ncbi.nlm.nih.gov/pubmed/8670804
Shergalis, A. G., Hu, S., Bankhead, A., & Neamati, N. (2020). Role of the ERO1-PDI interaction in oxidative protein folding and disease. Pharmacology and Therapeutics (Vol. 210). Elsevier Inc. https://doi.org/10.1016/j.pharmthera.2020.107525
Shoulders, M. D., Ryno, L. M., Genereux, J. C., Moresco, J. J., Tu, P. G., Wu, C., Yates, J. R., Su, A. I., Kelly, J. W., & Wiseman, R. L. (2013). Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse ER Proteostasis Environments. Cell Reports, 3(4), 1279–1292. https://doi.org/10.1016/j.celrep.2013.03.024
Simmons, G., Gosalia, D. N., Rennekamp, A. J., Reeves, J. D., Diamond, S. L., & Bates, P. (2005). Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proceedings of the National Academy of Sciences of the United States of America, 102(33), 11876–11881. https://doi.org/10.1073/pnas.0505577102
Siordia, J. A. (2020). Epidemiology and clinical features of COVID-19: A review of current literature. Journal of Clinical Virology (Vol. 127). Elsevier B.V. https://doi.org/10.1016/j.jcv.2020.104357
Smith, J. A., Schmechel, S. C., Raghavan, A., Abelson, M., Reilly, C., Katze, M. G., Kaufman, R. J., Bohjanen, P. R., & Schiff, L. A. (2006). Reovirus Induces and Benefits from an Integrated Cellular Stress Response. Journal of Virology, 80(4), 2019–2033. https://doi.org/10.1128/jvi.80.4.2019-2033.2006
Smith, M., & Wilkinson, S. (2017). ER homeostasis and autophagy. Essays in Biochemistry (Vol. 61, Issue 6, pp. 625–635). Portland Press Ltd. https://doi.org/10.1042/EBC20170092
Snijder, E. J., van der Meer, Y., Zevenhoven-Dobbe, J., Onderwater, J. J. M., van der Meulen, J., Koerten, H. K., & Mommaas, A. M. (2006a). Ultrastructure and Origin of Membrane Vesicles Associated with the Severe Acute Respiratory Syndrome Coronavirus Replication Complex. Journal of Virology, 80(12), 5927–5940. https://doi.org/10.1128/jvi.02501-05
Snijder, E. J., van der Meer, Y., Zevenhoven-Dobbe, J., Onderwater, J. J. M., van der Meulen, J., Koerten, H. K., & Mommaas, A. M. (2006b). Ultrastructure and Origin of Membrane Vesicles Associated with the Severe Acute Respiratory Syndrome Coronavirus Replication Complex. Journal of Virology, 80(12), 5927–5940. https://doi.org/10.1128/jvi.02501-05
So, J. S. (2018). Roles of endoplasmic reticulum stress in immune responses. Molecules and Cells (Vol. 41, Issue 8, pp. 705–716). Korean Society for Molecular and Cellular Biology. https://doi.org/10.14348/molcells.2018.0241
Kim, S. J., Mitra, D., Salerno, J. R., & Hegde, R. S. (2002). Signal sequences control gating of the protein translocation channel in a substrate-specific manner. Developmental Cell, 2(2), 207–217. https://doi.org/10.1016/s1534-5807(01)00120-4
Sriburi, R., Jackowski, S., Mori, K., & Brewer, J. W. (2004). XBP1: A link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. Journal of Cell Biology, 167(1), 35–41. https://doi.org/10.1083/jcb.200406136
Supasa, P., Zhou, D., Dejnirattisai, W., Liu, C., Mentzer, A. J., Ginn, H. M., Zhao, Y., Duyvesteyn, H. M. E., Nutalai, R., Tuekprakhon, A., Wang, B., Paesen, G. C., Slon-Campos, J., López-Camacho, C., Hallis, B., Coombes, N., Bewley, K. R., Charlton, S., Walter, T. S., … Screaton, G. R. (2021). Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell, 184(8), 2201-2211.e7. https://doi.org/10.1016/j.cell.2021.02.033
Szegezdi, E., Logue, S. E., Gorman, A. M., & Samali, A. (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Reports (Vol. 7, Issue 9, pp. 880–885). https://doi.org/10.1038/sj.embor.7400779
Teuwen, L. A., Geldhof, V., Pasut, A., & Carmeliet, P. (2020). COVID-19: the vasculature unleashed. Nature Reviews Immunology (Vol. 20, Issue 7, pp. 389–391). Nature Research. https://doi.org/10.1038/s41577-020-0343-0
Tian, S., Hu, W., Niu, L., Liu, H., Xu, H., & Xiao, S. Y. (2020). Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. Journal of Thoracic Oncology, 15(5), 700–704. https://doi.org/10.1016/j.jtho.2020.02.010
Urban, C. F., Ermert, D., Schmid, M., Abu-Abed, U., Goosmann, C., Nacken, W., Brinkmann, V., Jungblut, P. R., & Zychlinsky, A. (2009). Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathogens, 5(10). https://doi.org/10.1371/journal.ppat.1000639
Veras, F. P., Pontelli, M. C., Silva, C. M., Toller-Kawahisa, J. E., de Lima, M., Nascimento, D. C., Schneider, A. H., Caetité, D., Tavares, L. A., Paiva, I. M., Rosales, R., Colón, D., Martins, R., Castro, I. A., Almeida, G. M., Lopes, M. I. F., Benatti, M. N., Bonjorno, L. P., Giannini, M. C., … Cunha, F. Q. (2020). SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. Journal of Experimental Medicine, 217(12). https://doi.org/10.1084/jem.20201129
Versteeg, G. A., van de Nes, P. S., Bredenbeek, P. J., & Spaan, W. J. M. (2007). The Coronavirus Spike Protein Induces Endoplasmic Reticulum Stress and Upregulation of Intracellular Chemokine mRNA Concentrations. Journal of Virology, 81(20), 10981–10990. https://doi.org/10.1128/jvi.01033-07
V’kovski, P., Kratzel, A., Steiner, S., Stalder, H., & Thiel, V. (2021a). Coronavirus biology and replication: implications for SARS-CoV-2. Nature Reviews Microbiology (Vol. 19, Issue 3, pp. 155–170). Nature Research. https://doi.org/10.1038/s41579-020-00468-6
V’kovski, P., Kratzel, A., Steiner, S., Stalder, H., & Thiel, V. (2021b). Coronavirus biology and replication: implications for SARS-CoV-2. Nature Reviews Microbiology (Vol. 19, Issue 3, pp. 155–170). Nature Research. https://doi.org/10.1038/s41579-020-00468-6
Wang, M., & Kaufman, R. J. (2016). Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature (Vol. 529, Issue 7586, pp. 326–335). Nature Publishing Group. https://doi.org/10.1038/nature17041
Wang, Q., Groenendyk, J., & Michalak, M. (2015). Glycoprotein quality control and endoplasmic reticulum stress. Molecules (Vol. 20, Issue 8, pp. 13689–13704). MDPI AG. https://doi.org/10.3390/molecules200813689
Wu, H. Y., & Brian, D. A. (2010). Subgenomic messenger RNA amplification in coronaviruses. Proceedings of the National Academy of Sciences of the United States of America, 107(27), 12257–12262. https://doi.org/10.1073/pnas.1000378107
Wu, J., Rutkowski, D. T., Dubois, M., Swathirajan, J., Saunders, T., Wang, J., Song, B., Yau, G. D. Y., & Kaufman, R. J. (2007). ATF6α Optimizes Long-Term Endoplasmic Reticulum Function to Protect Cells from Chronic Stress. Developmental Cell, 13(3), 351–364. https://doi.org/10.1016/j.devcel.2007.07.005
Yamanka, T., Kuroki, M., Matsuo, Y., & Matsuoka, Y. (1996). Analysis of heterophilic cell adhesion mediated by CD66b and CD66c using their soluble recombinant proteins. Biochemical and Biophysical Research Communications, 219(3), 842–847. https://doi.org/10.1006/bbrc.1996.0320
Yang, H., & Rao, Z. (2021). Structural biology of SARS-CoV-2 and implications for therapeutic development. Nature Reviews Microbiology (Vol. 19, Issue 11, pp. 685–700). Nature Research. https://doi.org/10.1038/s41579-021-00630-8
Yang, Y., Wu, Y., Meng, X., Wang, Z., Younis, M., Liu, Y., Wang, P., & Huang, X. (2022). SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK. Cell Death and Differentiation, 29(7), 1395–1408. https://doi.org/10.1038/s41418-022-00928-x
Zhang, C., Zheng, W., Huang, X., Bell, E. W., Zhou, X., & Zhang, Y. (2020). Protein Structure and Sequence Reanalysis of 2019-nCoV Genome Refutes Snakes as Its Intermediate Host and the Unique Similarity between Its Spike Protein Insertions and HIV-1. Journal of Proteome Research, 19(4), 1351–1360. https://doi.org/10.1021/acs.jproteome.0c00129
Zhang, J., Guo, J., Yang, N., Huang, Y., Hu, T., & Rao, C. (2022). Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death and Disease (Vol. 13, Issue 12). Springer Nature. https://doi.org/10.1038/s41419-022-05444-x
Zhang, Z., Zheng, Y., Niu, Z., Zhang, B., Wang, C., Yao, X., Peng, H., Franca, D. N., Wang, Y., Zhu, Y., Su, Y., Tang, M., Jiang, X., Ren, H., He, M., Wang, Y., Gao, L., Zhao, P., Shi, H., … Sun, Q. (2021). SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination. Cell Death and Differentiation, 28(9), 2765–2777. https://doi.org/10.1038/s41418-021-00782-3
Zhou, P., Yang, X. Lou, Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., Chen, H. D., Chen, J., Luo, Y., Guo, H., Jiang, R. Di, Liu, M. Q., Chen, Y., Shen, X. R., Wang, X., … Shi, Z. L. (2020a). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273. https://doi.org/10.1038/s41586-020-2012-7
Zhou, P., Yang, X. Lou, Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., Chen, H. D., Chen, J., Luo, Y., Guo, H., Jiang, R. Di, Liu, M. Q., Chen, Y., Shen, X. R., Wang, X., … Shi, Z. L. (2020b). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273. https://doi.org/10.1038/s41586-020-2012-7
Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G. F., & Tan, W. (2020). A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine, 382(8), 727–733. https://doi.org/10.1056/nejmoa2001017