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

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 <i>IFN-β</i> expression. TonEBP NT competed away NF-κB binding to the PRD II domain on the <i>IFN-β</i> promoter. A TonEBP mutant resistant to the cleavage by NSP5 did not promote the viral expansion nor suppress the <i>IFN-β</i> expression. These results demonstrate that HCoVs use a common strategy of targeting TonEBP to suppress the host immune defense.