Upregulation of the chemokine (C-C motif) ligand 2 via a severe acute respiratory syndrome coronavirus spike-ACE2 signaling pathway.
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 IkappaBalpha-NF-kappaB 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.
Chen
I-Yin
IY
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chang
Shin C
SC
Wu
Hung-Yi
HY
Yu
Ting-Chun
TC
Wei
Wen-Chin
WC
Lin
Shiming
S
Chien
Chung-Liang
CL
Chang
Ming-Fu
MF
D000085962:Angiotensin-Converting Enzyme 2; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000821:virology; D020869:Gene Expression Profiling; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D015398:Signal Transduction; D064370:Spike Glycoprotein, Coronavirus; D015854:Up-Regulation; D014759:Viral Envelope Proteins / Q000276:immunology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2