Broad Impact of Exchange Protein Directly Activated by cAMP 2 (EPAC2) on Respiratory Viral Infections.

Abstract

The recently discovered exchange protein directly activated by cAMP (EPAC), compared with protein kinase A (PKA), is a fairly new family of cAMP effectors. Soon after the discovery, EPAC has shown its significance in many diseases including its emerging role in infectious diseases. In a recent study, we demonstrated that EPAC, but not PKA, is a promising therapeutic target to regulate respiratory syncytial virus (RSV) replication and its associated inflammation. In mammals, there are two isoforms of EPAC-EPAC1 and EPAC2. Unlike other viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) and Ebola virus, which use EPAC1 to regulate viral replication, RSV uses EPAC2 to control its replication and associated cytokine/chemokine responses. To determine whether EPAC2 protein has a broad impact on other respiratory viral infections, we used an EPAC2-specific inhibitor, MAY0132, to examine the functions of EPAC2 in human metapneumovirus (HMPV) and adenovirus (AdV) infections. HMPV is a negative-sense single-stranded RNA virus belonging to the family Pneumoviridae, which also includes RSV, while AdV is a double-stranded DNA virus. Treatment with an EPAC1-specific inhibitor was also included to investigate the impact of EPAC1 on these two viruses. We found that the replication of HMPV, AdV, and RSV and the viral-induced immune mediators are significantly impaired by MAY0132, while an EPAC1-specific inhibitor, CE3F4, does not impact or slightly impacts, demonstrating that EPAC2 could serve as a novel common therapeutic target to control these viruses, all of which do not have effective treatment and prevention strategies.

• Authors: Eun-Jin Choi, Wenzhe Wu, Xiaoyan Cong, Ke Zhang, Jiaqi Luo, Sha Ye, Pingyuan Wang, Adarsh Suresh, Uneeb Mohammad Ullah, Jia Zhou, Xiaoyong Bao
• Journal: Viruses (Viruses) Vol. 13 Issue 6 (06 21 2021) ISSN: 1999-4915 [Electronic] Switzerland
• PMID: 34205489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 6-fluoro-5,7-dibromo-2-methyl-1-formyl-1,2,3,4-tetrahydroquinoline
• Chemokines
• Guanine Nucleotide Exchange Factors
• Quinolines
• RAPGEF3 protein, human
• RAPGEF4 protein, human
• Cyclic AMP-Dependent Protein Kinases

Topics

• A549 Cells
• Adenoviridae (physiology)
• Cell Line
• Chemokines (immunology)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Epithelial Cells (drug effects, virology)
• Guanine Nucleotide Exchange Factors (antagonists & inhibitors, genetics, metabolism)
• HEK293 Cells
• Humans
• Metapneumovirus (physiology)
• Quinolines (pharmacology)
• Respiratory Syncytial Virus, Human (physiology)
• Virus Replication