SARS-CoV-2 strategically mimics proteolytic activation of human ENaC
Abstract
Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 65 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
The authors declare that there was no external funding for this work.
Reviewing Editor
- Gian Paolo Rossi, University of Padova, Italy
Publication history
- Received: May 5, 2020
- Accepted: May 25, 2020
- Accepted Manuscript published: May 26, 2020 (version 1)
- Version of Record published: July 8, 2020 (version 2)
Copyright
© 2020, Anand et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 19,592
- Page views
-
- 2,338
- Downloads
-
- 77
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cancer Biology
- Computational and Systems Biology
Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.
-
- Computational and Systems Biology
- Neuroscience
Humans make a number of choices when they walk, such as how fast and for how long. The preferred steady walking speed seems chosen to minimize energy expenditure per distance traveled. But the speed of actual walking bouts is not only steady, but rather a time-varying trajectory, which can also be modulated by task urgency or an individual’s movement vigor. Here we show that speed trajectories and durations of human walking bouts are explained better by an objective to minimize Energy and Time, meaning the total work or energy to reach destination, plus a cost proportional to bout duration. Applied to a computational model of walking dynamics, this objective predicts dynamic speed vs. time trajectories with inverted U shapes. Model and human experiment (N=10) show that shorter bouts are unsteady and dominated by the time and effort of accelerating, and longer ones are steadier and faster and dominated by steady-state time and effort. Individual-dependent vigor may be characterized by the energy one is willing to spend to save a unit of time, which explains why some may walk faster than others, but everyone may have similar-shaped trajectories due to similar walking dynamics. Tradeoffs between energy and time costs can predict transient, steady, and vigor-related aspects of walking.