SARS-CoV-2 8 binds IL17RA

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
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Elevated plasma level of interleukin-17 (IL17) has been reported in COVID-19 patients (reviewed in Shibabaw T 2020). Analysis of RNA-seq data from SARS-CoV-2 infection of different cells such as normal human bronchial epithelial (NHBE) cells, human lung carcinoma A549 cells, primary human airway epithelial (pHAE) cultures, cardiomyocytes and liver organoids and compared with other lung pathogenic infections revealed that SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses (Hasan MZ et al. 2021). Further, knockdown of IL17 receptor A (IL17RA) led to a decreased replication of SARS-CoV-2 in ACE2-expressing human alveolar basal epithelial A549 cells. Open reading frame 8 (ORF8 or 8) protein of SARS-CoV-2 has been implicated in the regulation of IL17 signaling pathway (Gordon DE et al. 2020; Lin X et al. 2021). Co-immunoprecipitation assay showed interaction between SARS-CoV-2 8 and human IL17RA upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Lin X et al. 2021). Glutathione s-transferase (gst) pull-down assay confirmed the direct interaction of viral 8 and IL17RA in vitro. Further, 8 (ORF8) interacted with endogenous IL17RA in ORF8-expressing HEK293T cells (Gordon DE et al. 2020) and in mouse peritoneal macrophages upon stimulation with His-tagged viral 8 (Lin X et al. 2021). This interaction is dependent on the functional domain fnIII_D2 of IL17RA (Lin X et al. 2021). Blocking IL17RA with an antibody reduced IL17 mediated inflammation in lung and liver in SARS-CoV2 ORF8 pseudovirus infected mice (Lin X et al. 2021). Further, infection with SARS-CoV-2 bearing a 382-nucleotide deletion in 8 produced lower concentrations of pro-inflammatory cytokines and chemokines in patients indicating an important role of viral 8 in the modulation of host antiviral response (Young BE et al. 2020). Cellular localization studies of expressed viral 8 in HeLa cells (Gordon DE et al. 2020) or in HEK293T cells (Zhang Y et al. 2021) in combination with enrichment analysis of SARS-CoV-2 8-interacting proteins (Gordon DE et al. 2020) revealed that the viral 8 protein localized in the endoplasmic reticulum (ER) and the lysosome. Patients with COVID-19 produce strong antibody response to SARS-CoV-2 8 suggesting that viral 8 is also secreted into the extracellular space (Hachim A et al. 2020). These data suggest that secreted SARS-CoV-2 8 binds to IL17RA and activates IL17 signaling pathway leading to an increased secretion of cytokines/chemokines thus contributing to cytokine storm during SARS-CoV-2 infection. Furthermore, SARS-CoV-2-host interactome and proteomics studies identified various human proteins as ORF8 binding partners (Gordon DE et al. 2020; Stukalov A et al. 2021), including factors involved in the TGF-β signalling pathway and components of the coagulation pathway such as FGA, PLAU, PLAT, SERPINE1 (Stukalov A et al. 2021). The contribution of ORF8 to a pro-inflammatory state and modulating coagulation cascade were predicted by in silico interactome appoach (Messina F et al. 2021). These data further support the functional importance of 8 (ORF8) in modulation of host immune responses.

This Reactome event shows binding of SARS-CoV-2 8 to IL17RA.

Literature References
PubMed ID Title Journal Year
33060197 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

Dunham, I, Kehrer, T, Southworth, DR, Alessi, DR, García-Sastre, A, Jura, N, Park, J, Liu, X, Frost, A, Li, Y, Kochs, G, Davies, P, Shokat, KM, Smith, AM, Foussard, H, Beltrao, P, Liu, Y, Koh, C, Vignuzzi, M, Tsui, TKM, Pollard, KS, Williams, DM, Merz, GE, Bouhaddou, M, Faust, B, Vallejo-Gracia, A, Tummino, TA, Li, F, Logue, J, Hemphill, KR, Guo, JZ, Barrio-Hernandez, I, Verba, KA, Shoichet, B, Pospiech, TH, Paulino, J, Ideker, T, Tse, E, Deshpande, I, Chio, CM, Fabius, JM, Geyer, A, Obernier, K, Safari, M, Pourmal, S, Simoneau, CR, Haas, P, Moreno, E, Zhang, Z, Cakir, M, Soucheray, M, Hüttenhain, R, Hiatt, J, Ott, M, Klesh, RJ, Rihn, S, Kortemme, T, Moritz, M, Burness, KA, Kaake, RM, Zhao, J, Carlson-Stevermer, J, Weston, S, Memon, D, Gordon, DE, Reid, E, Roth, TL, Shi, Y, Peden, AA, Azumaya, CM, Trenker, R, Weckstein, AR, Manglik, A, Vallet, T, Fraser, JS, Xu, J, White, KM, Braberg, H, Modak, M, Rathore, U, Batra, J, Wang, F, Hastie, CJ, Grosse, R, Toth, R, Zhang, Y, Li, YL, Goodman, N, Patel, AH, Basler, CF, Whitis, N, Keough, KC, QCRG Structural Biology Consortium, -, Elliott, M, Maures, T, Oki, J, Kim, K, Nowotny, C, Asarnow, D, Chazal, M, Gupta, M, Rassen, JA, McGregor, M, Ummadi, M, Khalid, MM, Flores, S, Frieman, MB, Baillie, C, Moss, FR, Weigang, S, Nguyen, HC, Biel, J, Doan, L, Brown, F, Silvas, JA, Palmarini, M, Chen, J, Saltzberg, D, Rojc, A, Pawar, KI, Giesel, DM, Dorward, M, Sangwan, S, Schulze-Gahmen, U, Ulferts, S, McGrath, M, Shun-Shion, AS, Holden, K, Sali, A, Thomas, PV, Kratochvil, HT, Johnson, C, Cakir, Z, Young, ID, Titus, EW, Schaefer, K, Haupt, R, Wilkinson, SG, Puchades, C, Agard, DA, Marrero, MC, Zoonomia Consortium, -, Peters, JK, Dunham, A, Lopez, KE, Nguyen, P, Bowen, A, Rizo, AN, Burke, D, Zhou, F, Naing, ZZC, Hoppe, N, Brilot, AF, Sun, M, Diwanji, D, Fozouni, P, Rosales, R, Rosenberg, OS, Cheng, Y, Abate, C, Diallo, A, Kuchenov, D, Raggett, S, Karim, MA, Thwin, AC, Berardi, F, Ghoussaini, M, Zhang, K, Stroud, RM, Yu, Z, Eckhardt, M, Braxton, JR, Leech, H, Pulido, EH, Chio, US, O'Meara, MJ, Melo, AA, Miorin, L, Owens, TW, Swaney, DL, Wu, D, Petsalaki, E, Lind, AL, Tutuncuoglu, B, Hodder, AJ, Li, J, Rezelj, VV, Haas, KM, Zhou, Y, Lo, M, Jang, G, Jureka, AS, Billesbølle, C, Krogan, NJ, Jin, M, Dickinson, MS, Jouvenet, N, Herrera, N, Campbell, MG, Lam, VL

Science 2020
33723527 ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

Yin, S, Xu, S, Zhao, Q, Wu, H, Zhang, S, Xiong, Y, Li, Z, Wang, X, Wang, P, Zhang, H, Zhang, J, Nian, W, Xue, W, Xing, N, Lin, X, Liu, H, Wang, Y, Fu, B

iScience 2021
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
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