A Gain-of-Function Cleavage of TonEBP by Coronavirus NSP5 to Suppress IFN-β Expression

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-09, Vol.13 (19), p.1614
• Main Authors: Park, Hyun, Lee, Sang Min, Jeong, Su Ji, Kweon, Yeong Cheon, Shin, Go Woon, Kim, Whi Young, Lee-Kwon, Whaseon, Park, Chan Young, Kwon, Hyug Moo
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Cloning; Coronavirus - metabolism; Coronaviruses; COVID-19; gain of function; Genomes; Glycerol; HEK293 Cells; Humans; IFN-β promoter; Immune system; Infections; innate immunity; Interferon-beta - genetics; Interferon-beta - metabolism; Membranes; Middle East respiratory syndrome; Mutagenesis; NF-kappa B - metabolism; NF-κB protein; Pandemics; Plasmids; Promoter Regions, Genetic - genetics; Protein Binding; Proteins; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Viral infections; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; β-Interferon
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13191614

Human coronaviruses (HCoVs) modify host proteins to evade the antiviral defense and sustain viral expansion. Here, we report tonicity-responsive enhancer (TonE) binding protein (TonEBP) as a cellular target of HCoVs. TonEBP was cleaved into N-terminal and C-terminal fragments (TonEBP NT and TonEBP CT, respectively) by NSP5 from all the HCoVs tested. This cleavage resulted in the loss of TonEBP's ability to stimulate the TonE-driven transcription. On the other hand, TonEBP NT promoted viral expansion in association with the suppression of expression. TonEBP NT competed away NF-κB binding to the PRD II domain on the promoter. A TonEBP mutant resistant to the cleavage by NSP5 did not promote the viral expansion nor suppress the expression. These results demonstrate that HCoVs use a common strategy of targeting TonEBP to suppress the host immune defense.