Iron in The Time of Coronavirus

 

Olga Protchenko and Caroline Philpott

The world’s attention is focused on the Covid-19 outbreak, in which SARS-CoV-2 has infected over 3 million people worldwide with high morbidity and mortality. While the pandemic is causing global health and socioeconomic disruption, nations are turning to their scientists for help. Now, many scientific institutions are committed to launching studies on this viral disease from different angles. Can the expertise of the BioIron community contribute to these efforts?

Iron biologists have long observed a link between iron and infection with a variety of microbial and viral pathogens; the links between iron and viral infection are both direct and indirect. Transferrin receptor 1 can serve as cell surface receptor for multiple viruses, iron-containing proteins are required for viral replication and packaging, and hepcidin regulation can affect patient outcomes in chronic viral infections (see (Drakesmith and Prentice, 2008) for an excellent review).

Our group has been studying the poly C-binding proteins (PCBPs) because of their capacity to bind and deliver iron to iron proteins in the cytosol. This family of proteins was initially identified for their RNA- and ssDNA-binding activity; subsequent studies have found them to be important host factors in RNA virus replication. PCBPs bind single-stranded nucleic acid and function in cellular RNA metabolism through interactions with C-rich sequences. RNA viruses, such as enterovirus 71, HCV, and poliovirus, contain C-rich regions and hijack PCBPs for their own replication. The binding of PCBPs to C-rich sequences in viral 5’ UTRs, internal ribosome entry sites (IRES) or programmed ribosomal frameshifting (PRF) sites (Li et al., 2019) are critical for viral replication.

Host iron proteins were identified in recent proteomics studies of SARS-CoV-2; among them are heme oxygenase 1, the heme transporter FLVCR, the iron-sulfur subunit B of succinate dehydrogenase SDHB, and the mitochondria-associated iron-sulfur protein CISD1 (Gordon et al., 2020). Studies of other RNA viruses have also identified components of the of viral replication machinery in association with host iron proteins, such as mitochondrial aconitase, the iron-containing, RNA helicase DDX1, and the iron chaperones PCBP1/2 (Lim et al., 2016).

Do both iron- and RNA-binding activities of PCBPs mediate their pro-viral properties? Have PCBPs evolved to simultaneously facilitate iron-protein activation and nucleic acid binding? If iron proteins involved in viral RNA processing are also dependent on PCBPs, then PCBPs may participate in several steps of viral replication through interaction with different host factors. Targeting host iron proteins important for virus replication cycle could be considered a strategy for antiviral treatment.

References

Drakesmith, H., and Prentice, A. (2008). Viral infection and iron metabolism. Nat Rev Microbiol 6, 541-552.

Gordon, D.E., Jang, G.M., Bouhaddou, M., Xu, J., Obernier, K., White, K.M., O’Meara, M.J., Rezelj, V.V., Guo, J.Z., Swaney, D.L., et al. (2020). A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature.

Li, Y., Firth, A.E., Brierley, I., Cai, Y., Napthine, S., Wang, T., Yan, X., Kuhn, J.H., and Fang, Y. (2019). Programmed -2/-1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily Conserved Mechanism. J Virol 93.

Lim, Y.X., Ng, Y.L., Tam, J.P., and Liu, D.X. (2016). Human Coronaviruses: A Review of Virus-Host Interactions. Diseases 4.