Cellular sensor DAP5 decodes

Background: Viral infection induces host cells to enter a state of "virus-induced senescence (VIS)", which provides a stable cellular environment for viral replication. However, it is unclear about the molecular mechanism of this process. Here, we identified cellular protein DAP5 and its N-terminal fragment DAP5 Methods: Upon SARS-CoV-2 infection, cellular apoptosis and senescence levels were assessed. This led to the identification of DAP5 as a pivotal proteolytic substrate that links viral protease activity to host cell fate determination. The specific cleavage site on DAP5 targeted by the non-structural protein 5 (NSP5) encoded by SARS-CoV-2 was mapped using Western Blot and Fluorescence Resonance Energy Transfer (FRET) analysis. The functional role of the resulting N-terminal fragment DAP5 Results: Viral infection-activated caspase 3 cleaves DAP5, which contributed to positive feedback loops, reinforcing apoptotic process. NSP5 interrupted the apoptotic process by NSP5-specific cleavage of DAP5 that led to the production of the N-terminal fragment DAP5 Conclusions: Our findings clarify the mechanism of SARS-CoV-2 induced VIS and establish a model of host cells inhibiting VIS through protein degradation and limiting viral replication, which provides a basis for subsequent immunological studies of emergent pathogenic microbial infection.