N-Glycosylation Network Construction and Analysis to Modify Glycans on the Spike (S) Glycoprotein of SARS-CoV-2
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Abstract
Background: The N-glycan structure and composition of the spike (S) protein of SARS-CoV-2 are pertinent to vaccine development and efficacy.
Methods: We reconstructed the glycosylation network based on previously published mass spectrometry data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 26 glycosyltransferase and glucosidase enzymes and could infer the pathway of glycosylation machinery based on glycans in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes—swainsonine or deoxynojirimycin for blocking mannosidase-II and indolizidine for blocking alpha-1,6-fucosyltransferase—to see how they would affect the biosynthesis network and the glycans that were synthesized.
Results: The N-glycan biosynthesis network of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Of the 26 enzymes, the following were involved—Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B3GalT, B4GalT, Man-II, SiaT, ST3GalI, ST3GalVI, and FucT8. Blocking specific enzymes resulted in a substantially modified glycan profile of SARS-CoV-2.
Conclusion: Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, are factors in the host response to the infection, vaccines, and antibodies. Heterogeneity in the N-glycan profile of the spike (S) protein and its potential effect on vaccine efficacy or adverse reactions to the vaccines remain unexplored. Here, we provide all the resources we generated—the glycans in the glycoCT xml format and the biosynthesis network for future work.
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SciScore for 10.1101/2020.06.23.167791: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Data from Zhang et al11 and Shajahan et al13 were both obtained from recombinant viral proteins expressed in HEK293 cells. HEK293suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers …
SciScore for 10.1101/2020.06.23.167791: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Data from Zhang et al11 and Shajahan et al13 were both obtained from recombinant viral proteins expressed in HEK293 cells. HEK293suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.06.23.167791: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Objective: To identify a putative N-glycan biosynthesis pathway of SARS-CoV-2 (HEK293 cell recombinant) from previously published mass spectrometric studies, and to identify what effect blocking some enzymes has on the overall glycoprotein profile. HEK293suggested: CLS Cat# 300192/p777_HEK293, CVCL_0045Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
- This heterogeneity can also affect the pathway that was chosen or the enzyme that was involved in …
SciScore for 10.1101/2020.06.23.167791: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Objective: To identify a putative N-glycan biosynthesis pathway of SARS-CoV-2 (HEK293 cell recombinant) from previously published mass spectrometric studies, and to identify what effect blocking some enzymes has on the overall glycoprotein profile. HEK293suggested: CLS Cat# 300192/p777_HEK293, CVCL_0045Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
- This heterogeneity can also affect the pathway that was chosen or the enzyme that was involved in the biosynthesis, which is a limitation in our current approach.
- Limitations: As mentioned, there are several more approaches to construct N-glycosylation pathways.
- In addition to that, this work being computational, is preliminary, and requires further computational and basic/pre-clinical/clinical work to identify the effect of simulated outcomes.
- We did not conduct protein dynamic modeling studies, to determine if the altered glycan affects the protein, and its downstream binding with mammalian receptors.
Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).
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