Covid proteins and mitochondria complex 1?
Browsing a January 2021 review on endothelial dysfunction and a potential role of chronic oxidative stress [1] that echoed much of what we’ve had to say about Cu/Zn turning on and off inflammasomes that produce IL1β. They discussed loss of Covid-19 receptor ACE2,more angiotensin II and more super oxide by way of NADPH oxidase. We addressed SOD3 vs the renin angiotensin system in a a slightly different context. These authors led us to ways of looking at Covid-19 proteins. They cited references of papers demonstrating interactions between Covid-19 proteins ORF9c and NSP7 and mitochondrial complex 1 protein NDUFB9 and assembling assisting proteins NDUFAF 1 & 2 that are proposed to be a source of oxygen radicals. [1].
Some of this is very speculative. If Covid-19 proteins ORF9c and NSP7 bind to Complex 1 proteins in the cell, do they prevent the assembly of complex 1, divert electrons to O2, or nothing at all? Follow this link to learn more about Complex1. Let’s take a look at the molecular fishing expedition.
The fishing expedition explained…
The ORF9c protein with an N-terminal biotin tag was expressed in A549 lung cancer epithelial cells. [1] Streptavidin has a very high affinity for biotin. was used to fish out the ORF9c and what ever mammalian proteins might be binding to it. The authors found that ORF9c binds to many membrane proteins in multiple cell organelles. [2] These authors also found that ORF9c decreased stress and immune related transcripts. [2]. It may be too soon to say if Long Covid is a low grade chronic infection.
Dominguez and coworkers quickly discovered that the ORF9c gene product associated with proteins in membranes of sub cellular organelles [2]. The authors addressed homology with other membrane associated proteins [2]. They also addressed how expressing this Covid-19 protein in lung epithelial cells, with or without the proeosome inhibitor MG132, affected gene transcription as well as proteins. [2] MG132 was used to inhibit protein degradation via the unfolded protein response. Below are some exerts from a very detailed paper that came to the conclusion that the protein product of the ORF9c gene may help Covid-19 evade the immune system. [2]
Netting cytokine and immune system evasion fish
Note that the control was a chimera of avidin and a small protein called green fluorescent protein. This serves as a nice control for epithelial cells responding to the translation of unnatural proteins. Changes in protein levels may be due to changes in the translation of mRNAs or to changes in degradation, hence the proteosome inhibitor MG132. STAT1 and STAT2 are are transcription factors that control the expression of interleukins among other proteins. The interferon reducible (IGI) family of proteins will not be addressed in this post. They are involved in Note the increase of cytokine transcripts as well as their receptors in GFP-avidin transfected cells versus ORF9c-avidin transfected cells. Note that the TAP1 protein is down regulated with or without proteosome inhibition. The Herpes virus evades the immune system by blocking the TAP1 protein from transporting viral peptides to the cell surface to alert circulating T cells. Down regulating this protein may have the same effect as blocking it.
References
- Chang, R., Mamun, A., Dominic, A., & Le, N. T. (2021). SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress. Frontiers in physiology, 11, 605908. Link
- Dominguez Andres, A., Feng, Y., Campos, A. R., Yin, J., Yang, C. C., James, B., Murad, R., Kim, H., Deshpande, A. J., Gordon, D. E., Krogan, N., Pippa, R., & Ronai, Z. A. (2020). SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells. bioRxiv : the preprint server for biology, 2020.08.18.256776. Cross Ref
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