COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein

Sepehr Ehsani

doi:10.1186/s13062-020-00275-2

Abstract

The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans through its inhibition of the iron-exporting protein ferroportin. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.

Highlights

BackgroundMuch research interest has been devoted to the spike (glyco) protein (forming the characteristic ‘corona’) and its importance in the development of vaccines and antivirals [17, 35]
The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors
As of the beginning of October 2020, 189 countries and regions are tackling the challenge of the pandemic caused by the novel coronavirus, with more than 35 million confirmed cases of infection worldwide [23, 33]

Summary

Background

Much research interest has been devoted to the spike (glyco) protein (forming the characteristic ‘corona’) and its importance in the development of vaccines and antivirals [17, 35]. The similarity reported here raises a potential and intriguing question of whether there could be mimicry of human hepcidin (structural, functional or otherwise), perhaps inside the host cell, by the TM-CT junction of the spike protein These possibilities should not be dismissed based on the mere phylogenetic gap between coronaviruses and vertebrate species. The influenza hemagglutinin glycoprotein appears to have a conserved ‘CXICI’ motif in its cytoplasmic tail domain [93, 128], and perhaps an ancestral spike protein with similar features convergently acquired hepcidin-like sequence motifs These are speculations and remain open questions. If the sequence similarity reported here is playing a significant role at the cellular level, could it be that, the cellular localizations appear to be different based on current knowledge, the SARS-CoV-2 spike protein cytoplasmic tail can partly mimic the structure of hepcidin and interact with ferroportin? Protein sequence: A unique but restricted sequence similarity exists between mature hepcidin and the cysteine-rich cytoplasmic tail of coronavirus spike proteins

Cytokine storm

Localization

Conclusion