SARS-CoV-1 9b binds TOMM70

Stable Identifier
R-HSA-9709787
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Human SARS coronavirus
Compartment
cytosol, mitochondrial outer membrane
ReviewStatus
5/5
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SARS-CoV-1 9b binds TOMM70
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The severe acute respiratory syndrome coronavirus type 1 (SARS)-CoV-1 open reading frame-9b protein (ORF-9b or 9b) is an accessory protein that may function during virus assembly (Xu K, et al. 2009) and may influence virus-host interplay and pathogenesis (Shi CS et al. 2014; Jiang HW et al. 2020). Structural studies revealed that viral 9b forms a 2-fold symmetric dimer constructed from two adjacent twisted β sheets with an amphipathic surface, and a central hydrophobic cavity that is thought to be involved in membrane attachment (Meier C et al. 2006). Self-interactions of 9b were also shown by co-immunoprecipitation (CoIP) assay in human embryonic kidney (HEK 293T) cells (von Brunn A et al. 2007).

SARS-CoV-1 9b is highly homologous to SARS-CoV-2 9b (Jiang HW et al. 2020; Gordon DE et al. 2020a). Both SARS-CoV-1 and SARS-CoV-2 9b proteins localize to the membrane of mitochondria to suppress host innate immunity (Shi CS et al. 2014; Jiang HW et al. 2020; Gordon DE et al. 2020a). Affinity purification using HEK 293T cells coupled with mass spectrometry (AP-MS) analysis identified direct interaction between the mitochondrial import receptor subunit TOM70 (TOMM70) protein and tagged 9b of SARS-CoV-1 and SARS-CoV-2 (Gordon DE et al. 2020a, b). Further, endogenous TOMM70 co-precipitated with Strep-tagged 9b from SARS-CoV-1 and SARS-CoV-2 expressed in both HEK293T and human lung epithelial A549 cells (Gordon DE et al. 2020a). Immunostaining of tagged SARS-CoV-1 9b and SARS-CoV-2 9b revealed that viral 9b co-localized with TOMM70 upon expression in HEK 293T cells or in a human epithelial cell line derived from cervical cancer (HeLaM) (Jiang HW et al. 2020; Gordon DE et al. 2020a). Similar findings were observed in SARS-CoV-2-infected human colorectal adenocarcinoma (Caco-2) cells (Gordon DE et al. 2020a). Thus, viral 9b:TOMM70 interaction is conserved between SARS-CoV-1 and SARS-CoV-2 (Jiang HW et al. 2020; Gordon DE et al. 2020a).

TOMM70 is a member of the TOM complex that transports cytosolic pre-proteins destined for the mitochondrial compartments (reviewed in Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The C-terminal tetratricopeptide repeat (TPR) motifs in TOMM70 recognizes the internal mitochondrial targeting signals (MTSs) of mitochondrial protein precursors in the cytosol and mediates their translocation to the mitochondria (reviewed in Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The molecular chaperone complexes of heat shock protein 90 kDa (HSP90) and HSP70 bind to the N-terminal TPR clamp domain of TOMM70 and thus facilitate delivery of precursor proteins to TOMM70 (Young JC et al. 2003; Zanphorlin LM et al. 2016). Further, TOMM70 is involved in the activation of antiviral immunity by interacting with the mitochondrial antiviral signaling protein (MAVS) (Liu XY et al. 2010). Association of TOMM70 with MAVS is thought to promote the recruitment of TBK1 and IRF3 to MAVS upon viral infection (Liu XY et al. 2010). Activated IRF3 translocates into the nucleus to induce the transcription of genes encoding type I interferons (IFN). SARS‑CoV-1 and SARS-CoV-2 9b localized to mitochondria and inhibited the MAVS-mediated production of type I IFNs by targeting TOMM70 (Jiang HW et al. 2020). Cryo–electron microscopy (cryo-EM) structure of the TOMM70:SARS-CoV-2 9b complex suggests that viral 9b binds to the substrate recognition site of TOMM70 thus competing with substrate proteins involved in the induction of type I IFN synthesis (Jiang HW et al. 2020; Gordon DE et al. 2020a; reviewed in Kreimendahl S & Joachim Rassow J 2020). Moreover, SARS-CoV-1 9b suppressed the MAVS-mediated signaling by recruiting poly(rC) binding protein 2 (PCBP2) and the HECT domain E3 ligase AIP4 (ITCH) which triggered the K48-linked polyubiquitination and subsequent degradation of MAVS via the proteasomal pathway (Shi CS et al. 2014).

This Reactome event shows SARS-CoV-1 9b binding to TOMM70.

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
32728199 SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

Zheng, YX, Tao, SC, Wang, XN, Chen, H, Xie, J, Meng, QF, Jiang, HW, Zhang, J, Qi, H, Zhang, HN, Han, ZG, Wang, PH, Li, Y

Cell Mol Immunol 2020
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
severe acute respiratory syndrome DOID:2945 SARS-CoV infection, SARS
Authored
Shamovsky, V  (2020-06-25)
Reviewed
D'Eustachio, P  (2021-01-26)
Created
Shamovsky, V  (2020-12-17)
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