PEDV evades host immunity through reciprocal stabilization of PLP2 and GSDMD-CT

Abstract

GSDMD-mediated pyroptosis is a critical component of the host innate immune defense against viral infection. While the pyroptosis-executing N-terminal domain of GSDMD (GSDMD-NT) has been extensively investigated, the role of the C-terminal domain (GSDMD-CT) remains largely unexplored. Building on our previous findings that GSDMD-CT degrades RIG-I and TBK1 to inhibit type I interferon (IFN-I) signaling, this study demonstrates that porcine GSDMD-CT inhibits IFN-I signaling and promotes porcine epidemic diarrhea virus (PEDV) replication. We found that the PEDV-encoded PLP2 protein directly interacts with GSDMD-CT, resulting in mutual stabilization. Mechanistically, PLP2 enhances GSDMD-CT stability by removing K48-linked polyubiquitination at residue K118, while GSDMD-CT promotes K11-linked ubiquitination at the K66 site of PLP2. This mutual stabilization creates a synergistic feedback loop that suppresses both pyroptosis and IFN-I signaling, ultimately facilitating robust PEDV replication. These findings provide novel insights into viral immune evasion mechanisms and establish a theoretical foundation for developing innovative strategies for viral prevention and control.