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(M) of SARS-Cov-2 Endomembrane systems are reorganized by ORF3a and Membrane (M) of SARS-CoV-2 Yun-Bin Lee1, Minkyo Jung2, Jeesoo Kim3, Myeong-Gyun Kang1, Chulhwan Kwak1,5, Jong-Seo Kim3,4,*, Ji- Young Mun2,*, Hyun-Woo Rhee1,4,* 1Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea 2Neural Circuit Research Group, Korea Brain Research Institute, 41062 Daegu, Republic of Korea 3Center for RNA research, Institute for Basic Science, Seoul 08826, Republic of Korea 4School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea 5Department of Chemistry, Ulsan National Institute of Science and Technology, 44919 Ulsan, Korea *Correspondence: [email protected], [email protected], [email protected]. Table of Contents Supplementary Figure 1-15-----------------------------------------------------------------------------------------S2-24 Supplementary Table 1-3------------------------------------------------------------------------------------------S25-29 -S1- A GFP V5 BF Merged + Pearson R V5 - = 0.64 GFP GFP - SEC61B ORF3a Pearson R = 0.61 Pearson R + V5 - = 0.57 GFP GFP - M SEC61B Pearson R = 0.64 B GFP Flag BF Merged + + Pearson R = 0.87 Flag - GFP GFP - ORF3a ORF3a Pearson R = 0.80 + Pearson R = 0.67 Flag - GFP GFP - ORF6 ORF6 Pearson R = 0.64 + Pearson R Flag = 0.91 - GFP GFP - ORF7b ORF7b Pearson R = 0.90 + Pearson R = 0.91 Flag - GFP GFP - M M Pearson R = 0.89 Supplementary Figure 1. Additional confocal microscopy images of GFP-tagged vPOIs of SARS-CoV-2 (a) Confocal microscopy images of ORF3a-GFP (left) and M-GFP (right) with SEC61B-V5-TurboID. SEC61B-V5- TurboID was visualized by Anti-V5 antibody (AF647-conjugated secondary antibody, Cy5 fluorescence channel). Pearson correlation values were calculated between different fluorescent channel images. BF: bright field, Scale bars: 10 μm. (b) Confocal microscopy images of co-expressed vPOI-GFP and vPOI-Flag. Flag-conjugated vPOIs (ORF3a, ORF6, ORF7b, M of SARS-CoV-2) were visualized by using Anti-Flag antibody (AF647-conjugated secondary antibody, Cy5 fluorescence channel) and GFP-conjugated vPOIs fluorescence was detected in GFP fluorescence channel. Pearson correlation values were calculated between different fluorescent channel images. BF: bright field, Scale bars: 10 μm. -S2- V5 SA BF V5 SA GFP BF TurboID-V5-GBP TurboID-V5-GBP + ORF3a-GFP V5 SA GFP BF TurboID-V5-GBP TurboID-V5-GBP + ORF6-GFP + M-GFP TurboID-V5-GBP TurboID-V5-GBP + N-GFP + ORF7b-GFP Supplementary Figure 2. Additional Confocal images of Figure 2B. Confocal microscopy images of GFP-conjugated vPOIs (M, N, ORF3a, ORF6 and ORF7b of SARS-CoV-2) and co-expressed TurboID-V5-GBP in HEK293-AD cells. TurboID-V5-GBP (TurboID-GBP) was visualized by anti-V5 antibody (AF568-conjugated, RFP fluorescence channel). and GFP fluorescence was detected in GFP fluorescence channel. Biotinylated proteins were visualized by AF647- conjugated streptavidin (Cy5 fluorescence channel). BF: bright field, Scale bars: 10 μm. -S3- S - S - S - S S - S - S - - S - S - - S - - - S - - S Supplementary Figure 3. Raw images of western blotting results from Figure 2. (A) Raw images of western blotting and Ponceau membrane stain results with size ladder from Figure 2c (WB: SA-HRP). (B) Raw images of western blotting and Ponceau membrane staining results with size ladder from Figure 2c (WB: anti-V5). Selected areas for Figure 2c are marked with red box. (C) Raw images of western blotting and Ponceau membrane staining results with size ladder from Figure 2d (WB: anti-GFP). -S4- A ORF3a protein topology B M protein topology Protter - visualize proteoforms Omasits et al., Bioinformatics. 2013 Nov 21. Supplementary Figure 4. Predicted transmembrane domain regions of ORF3a and M by Protter. (A) Membrane topology of ORF3a. (B) Membrane topology of M These data was obtained by using Protter (https://wlab.ethz.ch/protter/start/). N-glyco motif was shown with green box. -S5- Supplementary Figure 5. Additional EM images of ORF3a or M expressed HeLa cells. (A) Additional EM images of ORF3a-linker-V5-APEX2 transfected HeLa cells. Bright field image of DAB-stained ORF3a-APEX2 transfected HeLa cells were shown in left. An EM image of the cell shown in Figure 3c is marked with black box in a bright field image. Scale bars : 500 m - 1 μm. (B) Additional EM images of M-linker-V5-APEX2 transfected HeLa cells. An EM image of the cell shown in Figure 3d is marked with black box in the bright field image. Untransfected cell was also shown with red box. Mitochondria is indicated as “m”, respectively (b–d). Scale bars: 1 μm. (C) CLEM images of ORF3a-GFP transfected HeLa cells. Scale bars: 1 μm. Distinct membrane structures were observed with higher magnification. Magnified area are marked with various color boxes.) Cubic membranes are indicated as “CM”. (D) CLEM images of M-GFP transfected HeLa cells. Electron-dense autophagic vesicles are marked with green arrows. Scale bars: 1 μm. -S6- A Untransfected A549 cell ER G L m m ER : ER, M : mitochondria, L : ly sosome, G : Golgi B A549 : SEC61B-APEX2 C A549 : APEX2 Supplementary Figure 6. EM images of control samples of A549 cells. (A) EM images of non-transfected A549 cells. Scale bars: 2 μm. (B) EM images of SEC61B-APEX2 transfected A549 cells. Scale bars: 1 - 2 μm. (C) EM images of APEX2 transfected cells. Scale bars: 1 - 2 μm. -S7- A Rep #1 Rep #2 Rep #3 31 31 31 29 29 29 27 27 27 25 25 25 23 23 23 21 y = x 21 y = 1.0298x 21 y = 0.9987x 19 R² = 1 19 R² = 0.7773 19 R² = 0.7378 17 17 17 Rep #1 Rep 15 15 15 13 13 13 ctrlrep #2 log 2 intensity ctrlrep #3 log 2 intensity ctrlrep #1 log 2 intensity 13 18 23 28 33 13 18 23 28 33 13 18 23 28 33 ctrl rep #1 log 2 intensity ctrl rep #1 log 2 intensity ctrl rep #1 log 2 intensity 31 31 33 29 29 27 27 28 25 25 23 23 GBP + GFP GBP y = x 23 21 21 - y = 0.9699x R² = 1 y = 0.9694x 19 R² = 0.8035 19 Rep #2 Rep 17 17 18 R² = 0.7882 15 15 13 13 ctrl #3 rep log 2intensity 13 ctrl rep #2 log 2 intensity ctrlrep #1 log 2 intensity 13 18 23 28 33 13 18 23 28 33 13 18 23 28 33 ctrl rep #2 log 2 intensity ctrl rep #2 log 2 intensity ctrl rep #2 log 2 intensity TurboID 31 31 31 29 29 29 27 27 27 25 25 25 23 23 23 21 21 21 y = 0.9996x y = x 19 19 y = 1.0302x 19 R² = 0.7242 R² = 1 Rep #3 Rep R² = 0.7413 17 17 17 15 15 15 13 13 13 ctrl rep #2 log 2 intensity ctrl rep #3 log 2 intensity ctrlrep #1 log 2 intensity 13 18 23 28 33 13 18 23 28 33 13 18 23 28 33 ctrl rep #3 log 2 intensity ctrl rep #3 log 2 intensity ctrl rep #3 log 2 intensity B Rep #1 Rep #2 Rep #3 33 33 33 28 28 28 23 23 23 y = 1.0538x y = x y = 0.9565x R² = 0.9186 R² = 1 18 R² = 0.677 18 18 Rep #1 Rep 13 13 ORF3a rep #3 log 2 intensity ORF3a rep #2 log 2 intensity ORF3a rep #1 log 2 intensity 13 18 23 28 13 13 18 23 28 13 18 23 28 GFP ORF3a rep #1 log 2 intensity ORF3a rep #1 log 2 intensity ORF3a rep #1 log 2 intensity - 33 33 33 28 28 28 23 23 23 y = x y = 1.0099x y = 0.9568x R² = 0.9856 Rep #2 Rep R² = 1 18 R² = 0.6789 18 18 13 13 13 ORF3a rep #3 log 2 intensity ORF3a rep #2 log 2 intensity ORF3a rep #1 log 2 intensity 13 18 23 28 13 18 23 28 GBP + ORF3a GBP 13 18 23 28 - ORF3a rep #2 log 2 intensity ORF3a rep #2 log 2 intensity ORF3a rep #2 log 2 intensity 33 33 33 28 28 28 TurboID 23 23 23 y = x Rep #3 Rep y = 0.9891x y = 0.9465x R² = 0.9855 R² = 1 18 R² = 0.9495 18 18 13 13 13 ORF3a rep #3 log 2 intensity ORF3a rep #1 log 2 intensity 13 18 23 28 ORF3a rep #2 log 2 intensity 13 18 23 28 13 18 23 28 ORF3a rep #3 log 2 intensity ORF3a rep #3 log 2 intensity ORF3a rep #3 log 2 intensity -S8- C Rep #1 Rep #2 Rep #3 33 31 31 29 29 28 27 27 25 25 23 23 23 y = x 21 21 R² = 1 19 19 18 17 y = 1.0018x 17 y = 0.9883x Rep #1 Rep 15 R² = 0.6414 15 R² = 0.7808 M rep M #2 log 2 intensity 13 13 rep M #3 log 2 intensity 13 M M rep #1 log 2 intensity 13 18 23 28 13 18 23 28 33 13 18 23 28 33 M rep #1 log 2 intensity M rep #1 log 2 intensity M rep #1 log 2 intensity GFP - 31 31 31 29 29 29 27 27 27 25 25 25 23 23 23 21 21 21 19 19 19 Rep #2 Rep GBP + M GBP 17 y = 0.9951x 17 y = x 17 y = 0.9866x - 15 R² = 0.6292 15 R² = 1 15 R² = 0.6083 M rep M #1 log 2 intensity M rep M #2 log 2 intensity 13 13 rep M #3 log 2 intensity 13 13 18 23 28 33 13 18 23 28 33 13 18 23 28 33 M rep #2 log 2 intensity M rep #2 log 2 intensity M rep #2 log 2 intensity 31 31 31 TurboID 29 29 29 27 27 27 25 25 25 23 23 23 21 21 21 Rep #3 Rep 19 19 19 17 y = 1.0101x 17 y = 1.0106x 17 y = x 15 R² = 0.7838 15 R² = 0.6378 15 R² = 1 M rep M #1 log 2 intensity M rep M #2 log 2 intensity 13 13 rep M #3 log 2 intensity 13 13 18 23 28 33 13 18 23 28 33 13 18 23 28 33 M rep #3 log 2 intensity M rep #3 log 2 intensity M rep #3 log 2 intensity D ctrl : GFP + TurboID-GBP ORF3a-GFP + TurboID-GBP M-GFP + TurboID-GBP rep #1 rep #2 rep #3 rep #1 rep #2 rep #3 rep #1 rep #2 rep #3 rep #1 1 0.924343 0.9441 0.484594 0.428742 0.291283 0.266151 0.210742 0.19369 ctrl : GFP + TurboID-GBP rep #2 0.924343 1 0.976369 0.581784 0.489374 0.396407 0.325799 0.262611 0.226385 rep #3 0.9441 0.976369 1 0.559304 0.454481 0.333395 0.294569 0.216243 0.180331 rep #1 0.484594 0.581784 0.559304 1 0.845807 0.845415 0.869613 0.768219 0.751899 ORF3a-GFP + TurboID-GBP rep #2 0.428742 0.489374 0.454481 0.845807 1 0.93272 0.780329 0.833266 0.765891 rep #3 0.291283 0.396407 0.333395 0.845415 0.93272 1 0.853849 0.887966 0.872773 rep #1 0.266151 0.325799 0.294569 0.869613 0.780329 0.853849 1 0.881657 0.878903 M-GFP + TurboID-GBP rep #2 0.210742 0.262611 0.216243 0.768219 0.833266 0.887966 0.881657 1 0.907887 rep #3 0.19369 0.226385 0.180331 0.751899 0.765891 0.872773 0.878903 0.907887 1
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