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Upregulation of the Chemokine (C-C Motif) Ligand 2 via a Severe Acute Respiratory Syndrome Coronavirus Spike-ACE2 Signaling Pathway
Open accessAbstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) was identified to be the causative agent of SARS with atypical pneumonia. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV. It is not clear whether ACE2 conveys signals from the cell surface to the nucleus and regulates expression of cellular genes upon SARS-CoV infection. To understand the pathogenesis of SARS-CoV, human type II pneumocyte (A549) cells were incubated with the viral spike protein or with SARS-CoV virus-like particles containing the viral spike protein to examine cytokine modulation in lung cells. Results from oligonucleotide-based microarray, real-time PCR, and enzyme-linked immunosorbent assays indicated an upregulation of the fibrosis-associated chemokine (C-C motif) ligand 2 (CCL2) by the viral spike protein and the virus-like particles. The upregulation of CCL2 by SARS-CoV spike protein was mainly mediated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and AP-1 but not the IκBα-NF-κB signaling pathway. In addition, Ras and Raf upstream of the ERK1/2 signaling pathway were involved in the upregulation of CCL2. Furthermore, ACE2 receptor was activated by casein kinase II-mediated phosphorylation in cells pretreated with the virus-like particles containing spike protein. These results indicate that SARS-CoV spike protein triggers ACE2 signaling and activates fibrosis-associated CCL2 expression through the Ras-ERK-AP-1 pathway.
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“Upregulation of the fibrosis-associated chemokine CCL2 was shown to be mediated by ERK1/2 in human lung A549 epithelial cells incubated with SARS-CoV spike (S) protein or SARS virus-like particles (VLPs) (25).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [25]
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Metadata
- Authors
- Chen, I.-Y., Chang, S. C., Wu, H.-Y., Yu, T.-C., Wei, W.-C., Lin, S., Chien, C.-L., & Chang, M.-F.
- Affiliations
- Institute of Biochemistry and Molecular Biology
- Institute of Microbiology
- Center for Optoelectronic Biomedicine
- National Taiwan University (TW)
- Corresponding author
- Chang, Shin C.
- Chang, Ming-Fu
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2010-08
- Volume
- 84
- Issue
- 15
- Pages
- 7703-7712
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC2897593
- OpenAlex
- W2096549714
- Cited by
- 141
- References
- 45
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 12 · 2022: 22 · 2021: 30 · 2020: 42 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- Academia Sinica
- National Taiwan University
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- SARS-CoV, ACE2 receptor, spike protein, MCP-1, ERK signaling, AP-1, RAS/RAF pathway, casein kinase 2, pulmonary fibrosis, A549 cells, SARS pathogenesis
- MeSH terms
- Angiotensin-Converting Enzyme 2, Cell Line, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Humans, Peptidyl-Dipeptidase A, Membrane Glycoproteins, Viral Envelope Proteins, Signal Transduction, Up-Regulation, Chemokine CCL2, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Severe acute respiratory syndrome-related coronavirus, Spike Glycoprotein, Coronavirus
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