Table 1 Points of similarity and divergence between hepcidin and the coronavirus spike protein cytoplasmic domain based on current knowledge of the viral protein and its pathobiology (see main text for references)

1. Protein sequence: A unique but restricted sequence similarity exists between mature hepcidin and the cysteine-rich cytoplasmic tail of coronavirus spike proteins.

1. Protein length and domains: Coronavirus spike proteins are much larger, multi-domain, proteins compared to the relatively short-length hepcidin proteins.

2. Post-translational processing: The proprotein convertase furin cleaves prohepcidin, and has been reported to also activate (the ectodomain of) the SARS-CoV-2 spike protein.

2. Post-translational modification: Cysteines in the cytoplasmic tail of coronavirus spike proteins are thought to be palmitoylation acceptor residues, and this modification has thus far not been reported to be reversible. Cysteines in hepcidin are used to form disulfide bonds.

3. Cytokine storm: IL-6-mediated inflammatory responses have been reported in COVID-19 patients. Hepcidin production in the liver is induced by IL-6 and is well-studied in the context of the anemia of inflammation. In addition, COVID-19 may be associated with a Kawasaki-disease-like systemic vasculitis manifestation in children, and hepcidin levels have also been suggested as a biomarker for Kawasaki disease.

3. Localization: Hepcidin is thought to interact with its main (iron-bound) interactor, ferroportin, extracellularly, whereas the spike protein cytoplasmic tail does not face the environment outside the viral membrane. (However, the cytoplasmic tail associates with the plasma membrane itself aided by its palmitoylation modifications, and hepcidin may interact with ferroportin close to ferroportin’s transmembrane regions in addition to extracellular residues.)

4. Hypoxia/Hypoxemia: COVID-19 may lead to symptoms resembling, but differentiable from, altitude illness, and hepcidin expression levels have also been studied in the context of high-altitude acclimatization.